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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. </p></div><div class="messagearea bk_noprnt" style="margin-bottom:1.3846em "><ul class="messages"><li class="info icon"><span class="icon">By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.</span></li></ul></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="Table of Contents Page" href="/books/n/mboc4/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-mboc4-lrg.png" alt="Cover of Molecular Biology of the Cell" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>Molecular Biology of the Cell. 4th edition.</h2><a data-jig="ncbitoggler" href="#__NBK26926_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK26926_dtls__"><div>Alberts B, Johnson A, Lewis J, et al.</div><div>New York: <a href="http://www.garlandscience.com/textbooks/0815341059.asp" ref="pagearea=page-banner&targetsite=external&targetcat=link&targettype=publisher">Garland Science</a>; 2002.</div></div><div class="half_rhythm"></div><div class="bk_noprnt"><form method="get" action="/books/n/mboc4/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search this book" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search this book" submit="false" style="padding: 0.1em 0.4em;" /></div></form></div></div></div></div></div>
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<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK26926_"><span class="title" itemprop="name">T Cells and MHC Proteins</span></h1></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><p>The diverse responses of T cells are collectively called <i>cell-mediated immune reactions</i>. This is to distinguish them from antibody responses, which, of course, also depend on cells (B cells). Like antibody responses, T cell responses are exquisitely <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>-specific, and they are at least as important as antibodies in defending vertebrates against infection. Indeed, most adaptive immune responses, including antibody responses, require helper T cells for their initiation. Most importantly, unlike B cells, T cells can help eliminate pathogens that reside inside host cells. Much of the rest of this chapter is concerned with how T cells accomplish this feat.</p><p>T cell responses differ from B cell responses in at least two crucial ways. First, T cells are activated by foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> to proliferate and differentiate into effector cells only when the antigen is displayed on the surface of antigen-presenting cells in peripheral lymphoid organs. The T cells respond in this manner because the form of antigen they recognize is different from that recognized by B cells. Whereas B cells recognize intact antigen, T cells recognize fragments of <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> antigens that have been partly degraded inside the <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a>. The peptide fragments are then carried to the surface of the presenting cell on special molecules called <i><a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins</i>, which present the fragments to T cells. The second difference is that, once activated, effector T cells act only at short range, either within a secondary <a class="def" href="/books/n/mboc4/A4754/def-item/A5412/">lymphoid organ</a> or after they have migrated into a site of infection. They interact directly with another cell in the body, which they either kill or signal in some way (we shall refer to such cells as <i>target cells).</i> Activated B cells, by contrast, secrete antibodies that can act far away.</p><p>There are two main classes of T cells—cytotoxic T cells and helper T cells. Effector <i>cytotoxic T cells</i> directly kill cells that are infected with a <a class="def" href="/books/n/mboc4/A4754/def-item/A5926/">virus</a> or some other intracellular <a class="def" href="/books/n/mboc4/A4754/def-item/A5603/">pathogen</a>. Effector <i>helper T cells,</i> by contrast, help stimulate the responses of other cells—mainly macrophages, B cells, and cytotoxic T cells.</p><p>In this <a class="def" href="/books/n/mboc4/A4754/def-item/A5785/">section</a>, we describe these two classes of T cells and their respective functions. We discuss how they recognize foreign antigens on the surface of <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>-presenting cells and target cells and consider the crucial part played by <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins in the recognition process. Finally, we describe how T cells are selected during their <a class="def" href="/books/n/mboc4/A4754/def-item/A5071/">development</a> in the thymus to ensure that only cells with potentially useful receptors survive and mature. We begin by considering the nature of the cell-surface receptors that T cells use to recognize antigen.</p><div id="A4492"><h2 id="_A4492_">T Cell Receptors Are Antibodylike Heterodimers</h2><p>Because T cell responses depend on direct contact with an <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> or a target cell, the antigen receptors made by T cells, unlike antibodies made by B cells, exist only in <a class="def" href="/books/n/mboc4/A4754/def-item/A5438/">membrane</a>-bound form and are not secreted. For this reason, T cell receptors were difficult to isolate, and it was not until the 1980s that they were first identified biochemically. On both cytotoxic and helper T cells, the receptors are similar to antibodies. They are composed of two disulfide-linked <a class="def" href="/books/n/mboc4/A4754/def-item/A5658/">polypeptide</a> chains (called α and β), each of which contains two <a class="def" href="/books/n/mboc4/A4754/def-item/A5313/">Ig</a>-like domains, one variable and one constant (<a class="figpopup" href="/books/NBK26926/figure/A4493/?report=objectonly" target="object" rid-figpopup="figA4493" rid-ob="figobA4493">Figure 24-42A</a>). Moreover, the three-dimensional structure of the extracellular part of a T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> has been <a class="def" href="/books/n/mboc4/A4754/def-item/A5070/">determined</a> by x-ray diffraction, and it looks very much like one arm of a Y-shaped antibody <a class="def" href="/books/n/mboc4/A4754/def-item/A5486/">molecule</a> (<a class="figpopup" href="/books/NBK26926/figure/A4493/?report=objectonly" target="object" rid-figpopup="figA4493" rid-ob="figobA4493">Figure 24-42B</a>).
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4493" co-legend-rid="figlgndA4493"><a href="/books/NBK26926/figure/A4493/?report=objectonly" target="object" title="Figure 24-42" class="img_link icnblk_img figpopup" rid-figpopup="figA4493" rid-ob="figobA4493"><img class="small-thumb" src="/books/NBK26926/bin/ch24f42.gif" src-large="/books/NBK26926/bin/ch24f42.jpg" alt="Figure 24-42. A T cell receptor heterodimer." /></a><div class="icnblk_cntnt" id="figlgndA4493"><h4 id="A4493"><a href="/books/NBK26926/figure/A4493/?report=objectonly" target="object" rid-ob="figobA4493">Figure 24-42</a></h4><p class="float-caption no_bottom_margin">A T cell receptor heterodimer. (A) Schematic drawing showing that the receptor is composed of an α and a β polypeptide chain. Each chain is about 280 amino acids long and has a large extracellular part that is folded into two Ig-like domains—one <a href="/books/NBK26926/figure/A4493/?report=objectonly" target="object" rid-ob="figobA4493">(more...)</a></p></div></div><p>The pools of <a class="def" href="/books/n/mboc4/A4754/def-item/A5215/">gene</a> segments that encode the α and β chains are located on different chromosomes. Like antibody heavy-chain pools, the T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> pools contain separate <i>V, D,</i> and <i>J</i> gene segments, which are brought together by <a class="def" href="/books/n/mboc4/A4754/def-item/A5805/">site-specific recombination</a> during T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5071/">development</a> in the thymus. With one exception, all the mechanisms used by B cells to generate antibody diversity are also used by T cells to generate T cell receptor diversity. Indeed, the same <i>V(D)J</i> recombinase is used, including the RAG proteins discussed earlier. The mechanism that does not operate in T cell receptor diversification is <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>-driven somatic hypermutation. Thus, the affinity of the receptors remains low (<i><a class="def" href="/books/n/mboc4/A4754/def-item/A5365/">K</a></i><sub>a</sub> ~ 10<sup>5</sup>-10<sup>7</sup> liters/<a class="def" href="/books/n/mboc4/A4754/def-item/A5483/">mole</a>), even late in an <a class="def" href="/books/n/mboc4/A4754/def-item/A5319/">immune response</a>. We discuss later how various co-receptors and cell-cell adhesion mechanisms greatly strengthen the binding of a T cell to an <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> or a target cell, helping to compensate for the low affinity of the T cell receptors.</p><p>A small minority of T cells, instead of making α and β chains, make a different but related type of <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5277/">heterodimer</a>, composed of γ and δ chains. These cells arise early in <a class="def" href="/books/n/mboc4/A4754/def-item/A5071/">development</a> and are found mainly in epithelia (in the skin and gut, for example). Their functions are uncertain, and we shall not discuss them further.</p><p>As with <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> receptors on B cells, the T cell receptors are tightly associated in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5642/">plasma membrane</a> with a number of invariant membrane-bound proteins that are involved in passing the signal from an antigen-activated <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> to the cell interior. We discuss these proteins in more detail later. First, however, we need to consider how cytotoxic and helper T cells function and the special ways in which they recognize foreign antigen.</p></div><div id="A4494"><h2 id="_A4494_">Antigen-Presenting Cells Activate T Cells</h2><p>Before cytotoxic or helper T cells can kill or help their target cells, respectively, they must be activated to proliferate and differentiate into effector cells. This activation occurs in peripheral lymphoid organs on the surface of <a href="/books/n/mboc4/A4754/#A4833">antigen-presenting cells</a> that display foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> complexed with <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins on their surface.</p><p>There are three main types of <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>-presenting cells in peripheral lymphoid organs that can activate T cells—dendritic cells, macrophages, and B cells. The most potent of these are <a href="/books/n/mboc4/A4754/#A5065">dendritic cells</a> (<a class="figpopup" href="/books/NBK26926/figure/A4495/?report=objectonly" target="object" rid-figpopup="figA4495" rid-ob="figobA4495">Figure 24-43</a>), whose only known function is to present foreign antigens to T cells. Immature dendritic cells are located in tissues throughout the body, including the skin, gut, and respiratory tract. When they encounter invading microbes at these sites, they endocytose the pathogens or their products and carry them via the <a class="def" href="/books/n/mboc4/A4754/def-item/A5410/">lymph</a> to local lymph nodes or gut-associated lymphoid organs. The encounter with a <a class="def" href="/books/n/mboc4/A4754/def-item/A5603/">pathogen</a> induces the <a class="def" href="/books/n/mboc4/A4754/def-item/A5065/">dendritic cell</a> to mature from an antigen-capturing cell to an <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> that can activate T cells (see <a href="/books/n/mboc4/A4422/figure/A4427/?report=objectonly" target="object" class="figpopup" rid-figpopup="figA4427" rid-ob="figobA4427">Figure 24-5</a>).
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4495" co-legend-rid="figlgndA4495"><a href="/books/NBK26926/figure/A4495/?report=objectonly" target="object" title="Figure 24-43" class="img_link icnblk_img figpopup" rid-figpopup="figA4495" rid-ob="figobA4495"><img class="small-thumb" src="/books/NBK26926/bin/ch24f43.gif" src-large="/books/NBK26926/bin/ch24f43.jpg" alt="Figure 24-43. Immunofluorescence micrograph of a dendritic cell in culture." /></a><div class="icnblk_cntnt" id="figlgndA4495"><h4 id="A4495"><a href="/books/NBK26926/figure/A4495/?report=objectonly" target="object" rid-ob="figobA4495">Figure 24-43</a></h4><p class="float-caption no_bottom_margin">Immunofluorescence micrograph of a dendritic cell in culture. These crucial antigen-presenting cells derive their name from their long processes, or “dendrites.” The cell has been labelled with a monoclonal antibody that recognizes a surface <a href="/books/NBK26926/figure/A4495/?report=objectonly" target="object" rid-ob="figobA4495">(more...)</a></p></div></div><p>Antigen-presenting cells display three types of <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> molecules on their surface that have a role in activating a T cell to become an <a class="def" href="/books/n/mboc4/A4754/def-item/A5113/">effector cell</a>: (1) <i><a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins</i>, which present foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> to the T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a>, (2) <i>costimulatory proteins,</i> which bind to <a class="def" href="/books/n/mboc4/A4754/def-item/A5012/">complementary</a> receptors on the T cell surface, and (3) <i>cell-cell adhesion molecules,</i> which enable a T cell to bind to the <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> for long enough to become activated (<a class="figpopup" href="/books/NBK26926/figure/A4496/?report=objectonly" target="object" rid-figpopup="figA4496" rid-ob="figobA4496">Figure 24-44</a>).
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4496" co-legend-rid="figlgndA4496"><a href="/books/NBK26926/figure/A4496/?report=objectonly" target="object" title="Figure 24-44" class="img_link icnblk_img figpopup" rid-figpopup="figA4496" rid-ob="figobA4496"><img class="small-thumb" src="/books/NBK26926/bin/ch24f44.gif" src-large="/books/NBK26926/bin/ch24f44.jpg" alt="Figure 24-44. Three types of proteins on the surface of an antigen-presenting cell involved in activating a T cell." /></a><div class="icnblk_cntnt" id="figlgndA4496"><h4 id="A4496"><a href="/books/NBK26926/figure/A4496/?report=objectonly" target="object" rid-ob="figobA4496">Figure 24-44</a></h4><p class="float-caption no_bottom_margin">Three types of proteins on the surface of an antigen-presenting cell involved in activating a T cell. The invariant polypeptide chains that are stably associated with the T cell receptor are not shown. </p></div></div><p>Before discussing the role of <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins in presenting <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> to T cells, we consider the functions of the two major classes of T cells.</p></div><div id="A4497"><h2 id="_A4497_">Effector Cytotoxic T Cells Induce Infected Target Cells to Kill Themselves</h2><p>
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<a href="/books/n/mboc4/A4754/#A5056">Cytotoxic T cells</a> provide protection against intracellular pathogens such as viruses and some bacteria and parasites that multiply in the host-cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5053/">cytoplasm</a>, where they are sheltered from attack by antibodies. They provide this protection by killing the infected cell before the microbes can proliferate and escape from the infected cell to infect neighboring cells.</p><p>Once a <a class="def" href="/books/n/mboc4/A4754/def-item/A5056/">cytotoxic T cell</a> has been activated by an infected <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> to become an <a class="def" href="/books/n/mboc4/A4754/def-item/A5113/">effector cell</a>, it can kill any target cell infected with the same <a class="def" href="/books/n/mboc4/A4754/def-item/A5603/">pathogen</a>. When the effector T cell recognizes a microbial antigen on the surface of an infected target cell, it focuses its secretory apparatus on the target. We can observe this behavior by studying effector T cells bound to their targets: when labeled with anti-<a class="def" href="/books/n/mboc4/A4754/def-item/A5904/">tubulin</a> antibodies, the T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A4956/">centrosome</a> is seen to be oriented toward the point of contact with the target cell (<a class="figpopup" href="/books/NBK26926/figure/A4498/?report=objectonly" target="object" rid-figpopup="figA4498" rid-ob="figobA4498">Figure 24-45</a>). Moreover, antibody labeling shows that talin and other proteins that help link cell-surface receptors to cortical <a class="def" href="/books/n/mboc4/A4754/def-item/A4766/">actin</a> filaments are concentrated in the cortex of the T cell at the contact site. The aggregation of T cell receptors at the contact site apparently leads to a local alteration in the actin filaments in the <a class="def" href="/books/n/mboc4/A4754/def-item/A4935/">cell cortex</a>. A <a class="def" href="/books/n/mboc4/A4754/def-item/A5465/">microtubule</a>-dependent mechanism then moves the centrosome and its associated Golgi apparatus toward the contact site, focusing the killing machinery on the target cell. A similar cytoskeletal polarization is seen when an effector <a class="def" href="/books/n/mboc4/A4754/def-item/A5269/">helper T cell</a> interacts functionally with a target cell.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4498" co-legend-rid="figlgndA4498"><a href="/books/NBK26926/figure/A4498/?report=objectonly" target="object" title="Figure 24-45" class="img_link icnblk_img figpopup" rid-figpopup="figA4498" rid-ob="figobA4498"><img class="small-thumb" src="/books/NBK26926/bin/ch24f45.gif" src-large="/books/NBK26926/bin/ch24f45.jpg" alt="Figure 24-45. Effector cytotoxic T cells killing target cells in culture." /></a><div class="icnblk_cntnt" id="figlgndA4498"><h4 id="A4498"><a href="/books/NBK26926/figure/A4498/?report=objectonly" target="object" rid-ob="figobA4498">Figure 24-45</a></h4><p class="float-caption no_bottom_margin">Effector cytotoxic T cells killing target cells in culture. (A) Electron micrograph showing an effector cytotoxic T cell binding to the target cell. The cytotoxic T cells were obtained from mice immunized with the target cells, which are foreign tumor <a href="/books/NBK26926/figure/A4498/?report=objectonly" target="object" rid-ob="figobA4498">(more...)</a></p></div></div><p>Once bound to its target cell, a <a class="def" href="/books/n/mboc4/A4754/def-item/A5056/">cytotoxic T cell</a> can employ at least two strategies to kill the target, both of which operate by inducing the target cell to kill itself by undergoing <a class="def" href="/books/n/mboc4/A4754/def-item/A4839/">apoptosis</a> (discussed in Chapter 17). In killing an infected target cell, the cytotoxic T cell usually releases a pore-forming <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> called <b>perforin</b>, which is <a class="def" href="/books/n/mboc4/A4754/def-item/A5292/">homologous</a> to the complement component C9 (see <a href="/books/n/mboc4/A4674/figure/A4681/?report=objectonly" target="object" class="figpopup" rid-figpopup="figA4681" rid-ob="figobA4681">Figure 25-42</a>) and polymerizes in the target cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5642/">plasma membrane</a> to form transmembrane channels. Perforin is stored in secretory vesicles of the cytotoxic T cell and is released by local <a class="def" href="/books/n/mboc4/A4754/def-item/A5160/">exocytosis</a> at the point of contact with the target cell. The secretory vesicles also contain serine proteases, which are thought to enter the target cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5055/">cytosol</a> through the perforin channels. One of the proteases, called <i>granzyme B,</i> cleaves, and thereby activates, one or more members of the <i><a class="def" href="/books/n/mboc4/A4754/def-item/A4920/">caspase</a> family</i> of proteases that mediate apoptosis. These caspases then activate other caspases, producing a proteolytic cascade that helps kill the cell (discussed in Chapter 17) (<a class="figpopup" href="/books/NBK26926/figure/A4499/?report=objectonly" target="object" rid-figpopup="figA4499" rid-ob="figobA4499">Figure 24-46A</a>). Mice in which the perforin <a class="def" href="/books/n/mboc4/A4754/def-item/A5215/">gene</a> is inactivated cannot generate microbe-specific cytotoxic T cells and show increased susceptibility to certain viral and intracellular bacterial infections.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4499" co-legend-rid="figlgndA4499"><a href="/books/NBK26926/figure/A4499/?report=objectonly" target="object" title="Figure 24-46" class="img_link icnblk_img figpopup" rid-figpopup="figA4499" rid-ob="figobA4499"><img class="small-thumb" src="/books/NBK26926/bin/ch24f46.gif" src-large="/books/NBK26926/bin/ch24f46.jpg" alt="Figure 24-46. Two strategies by which effector cytotoxic T cells kill their target cells." /></a><div class="icnblk_cntnt" id="figlgndA4499"><h4 id="A4499"><a href="/books/NBK26926/figure/A4499/?report=objectonly" target="object" rid-ob="figobA4499">Figure 24-46</a></h4><p class="float-caption no_bottom_margin">Two strategies by which effector cytotoxic T cells kill their target cells. (A) The cytotoxic T cell (T<sub>C</sub>) releases perforin and proteolytic enzymes onto the surface of an infected target cell by localized exocytosis. The high concentration of Ca<sup>2+</sup> in <a href="/books/NBK26926/figure/A4499/?report=objectonly" target="object" rid-ob="figobA4499">(more...)</a></p></div></div><p>In the second killing strategy, the <a class="def" href="/books/n/mboc4/A4754/def-item/A5056/">cytotoxic T cell</a> also activates a death-inducing <a class="def" href="/books/n/mboc4/A4754/def-item/A4920/">caspase</a> cascade in the target cell but does it less directly. A homotrimeric <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> on the cytotoxic T cell surface called <b>Fas <a class="def" href="/books/n/mboc4/A4754/def-item/A5393/">ligand</a></b> binds to transmembrane <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> proteins on the target cell called <b>Fas</b>. The binding alters the Fas proteins so that their clustered cytosolic tails recruit procaspase-8 into the <a class="def" href="/books/n/mboc4/A4754/def-item/A5014/">complex</a> via an <a class="def" href="/books/n/mboc4/A4754/def-item/A4778/">adaptor protein</a>. The recruited procaspase-8 molecules cross-cleave and activate each other to begin the caspase cascade that leads to <a class="def" href="/books/n/mboc4/A4754/def-item/A4839/">apoptosis</a> (<a class="figpopup" href="/books/NBK26926/figure/A4499/?report=objectonly" target="object" rid-figpopup="figA4499" rid-ob="figobA4499">Figure 24-46B</a>). Cytotoxic T cells apparently use this killing strategy to help contain an <a class="def" href="/books/n/mboc4/A4754/def-item/A5319/">immune response</a> once it is well underway, by killing excessive effector lymphocytes, especially effector T cells: if the <a class="def" href="/books/n/mboc4/A4754/def-item/A5215/">gene</a> encoding either Fas or Fas ligand is inactivated by <a class="def" href="/books/n/mboc4/A4754/def-item/A5502/">mutation</a>, effector lymphocytes accumulate in vast numbers in the spleen and <a class="def" href="/books/n/mboc4/A4754/def-item/A5410/">lymph</a> nodes, which become enormously enlarged.</p></div><div id="A4500"><h2 id="_A4500_">Effector Helper T Cells Help Activate Macrophages, B Cells, and Cytotoxic T Cells</h2><p>In contrast to cytotoxic T cells, <a href="/books/n/mboc4/A4754/#A5269">helper T cells</a> are crucial for defense against both extracellular and intracellular pathogens. They help stimulate B cells to make antibodies that help inactivate or eliminate extracellular pathogens and their toxic products. They activate macrophages to destroy any intracellular <a class="def" href="/books/n/mboc4/A4754/def-item/A5603/">pathogen</a> multiplying within the <a class="def" href="/books/n/mboc4/A4754/def-item/A5420/">macrophage</a>'s phagosomes, and they help activate cytotoxic T cells to kill infected target cells.</p><p>Once a <a class="def" href="/books/n/mboc4/A4754/def-item/A5269/">helper T cell</a> has been activated by an <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> to become an <a class="def" href="/books/n/mboc4/A4754/def-item/A5113/">effector cell</a>, it can then help activate other cells. It does this both by secreting a variety of cytokines and by displaying costimulatory proteins on its surface. When activated by an antigen-presenting cell, a naïve helper T cell can differentiate into either of two distinct types of effector helper cell, called T<sub>H</sub>1 and T<sub>H</sub>2. <i>T</i><sub><i>H</i></sub><i>1 cells</i> mainly help activate macrophages and cytotoxic T cells, whereas <i>T</i><sub><i>H</i></sub><i>2 cells</i> mainly help activate B cells (<a class="figpopup" href="/books/NBK26926/figure/A4501/?report=objectonly" target="object" rid-figpopup="figA4501" rid-ob="figobA4501">Figure 24-47</a>). As we discuss later, the nature of the invading <a class="def" href="/books/n/mboc4/A4754/def-item/A5603/">pathogen</a> and the types of innate immune responses it elicits largely determine which type of helper T cell develops. This, in turn, determines the nature of the adaptive immune responses mobilized to fight the invaders.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4501" co-legend-rid="figlgndA4501"><a href="/books/NBK26926/figure/A4501/?report=objectonly" target="object" title="Figure 24-47" class="img_link icnblk_img figpopup" rid-figpopup="figA4501" rid-ob="figobA4501"><img class="small-thumb" src="/books/NBK26926/bin/ch24f47.gif" src-large="/books/NBK26926/bin/ch24f47.jpg" alt="Figure 24-47. Differentiation of naïve helper T cells into either TH1 or TH2 effector helper cells in a peripheral lymphoid organ." /></a><div class="icnblk_cntnt" id="figlgndA4501"><h4 id="A4501"><a href="/books/NBK26926/figure/A4501/?report=objectonly" target="object" rid-ob="figobA4501">Figure 24-47</a></h4><p class="float-caption no_bottom_margin">Differentiation of naïve helper T cells into either T<sub>H</sub>1 or T<sub>H</sub>2 effector helper cells in a peripheral lymphoid organ. The antigen-presenting cell and the characteristics of the pathogen that activated it mainly determine which type of effector <a href="/books/NBK26926/figure/A4501/?report=objectonly" target="object" rid-ob="figobA4501">(more...)</a></p></div></div><p>Before discussing how helper T cells function to activate macrophages, cytotoxic T cells, or B cells, we need to consider the crucial role of <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins in T cell responses.</p></div><div id="A4502"><h2 id="_A4502_">T Cells Recognize Foreign Peptides Bound to MHC Proteins</h2><p>As discussed earlier, both cytotoxic T cells and helper T cells are initially activated in peripheral lymphoid organs by recognizing foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> on the surface of an <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a>, usually a <a class="def" href="/books/n/mboc4/A4754/def-item/A5065/">dendritic cell</a>. The antigen is in the form of peptide fragments that are generated by the degradation of foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> antigens inside the antigen-presenting cell. The recognition process depends on the presence in the antigen-presenting cell of <b><a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins</b>, which bind these fragments, carry them to the cell surface, and present them there, along with a co-stimulatory signal, to the T cells. Once activated, effector T cells then recognize the same peptide-MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A5014/">complex</a> on the surface of the target cell they influence, which may be a B cell, a <a class="def" href="/books/n/mboc4/A4754/def-item/A5056/">cytotoxic T cell</a>, or an infected <a class="def" href="/books/n/mboc4/A4754/def-item/A5420/">macrophage</a> in the case of a <a class="def" href="/books/n/mboc4/A4754/def-item/A5269/">helper T cell</a>, or a <a class="def" href="/books/n/mboc4/A4754/def-item/A5926/">virus</a>-infected cell in the case of a cytotoxic T cell.</p><p><a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins are encoded by a large <a class="def" href="/books/n/mboc4/A4754/def-item/A5014/">complex</a> of genes called the <b>major histocompatibility complex (MHC)</b>. There are two main structurally and functionally distinct classes of MHC proteins: <i>class I MHC proteins,</i> which present foreign peptides to cytotoxic T cells, and <i>class II MHC proteins,</i> which present foreign peptides to helper cells (<a class="figpopup" href="/books/NBK26926/figure/A4503/?report=objectonly" target="object" rid-figpopup="figA4503" rid-ob="figobA4503">Figure 24-48</a>).
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4503" co-legend-rid="figlgndA4503"><a href="/books/NBK26926/figure/A4503/?report=objectonly" target="object" title="Figure 24-48" class="img_link icnblk_img figpopup" rid-figpopup="figA4503" rid-ob="figobA4503"><img class="small-thumb" src="/books/NBK26926/bin/ch24f48.gif" src-large="/books/NBK26926/bin/ch24f48.jpg" alt="Figure 24-48. Recognition by T cells of foreign peptides bound to MHC proteins." /></a><div class="icnblk_cntnt" id="figlgndA4503"><h4 id="A4503"><a href="/books/NBK26926/figure/A4503/?report=objectonly" target="object" rid-ob="figobA4503">Figure 24-48</a></h4><p class="float-caption no_bottom_margin">Recognition by T cells of foreign peptides bound to MHC proteins. Cytotoxic T cells recognize foreign peptides in association with class I MHC proteins, whereas helper T cells recognize foreign peptides in association with class II MHC proteins. In both <a href="/books/NBK26926/figure/A4503/?report=objectonly" target="object" rid-ob="figobA4503">(more...)</a></p></div></div><p>Before examining the different mechanisms by which <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> antigens are processed for display to the two main classes of T cells, we must look more closely at the <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins themselves, which have such an important role in T cell function.</p></div><div id="A4504"><h2 id="_A4504_">MHC Proteins Were Identified in Transplantation Reactions Before Their Functions Were Known</h2><p><a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins were initially identified as the main antigens recognized in <b>transplantation reactions</b>. When organ grafts are exchanged between adult individuals, either of the same species <i>(allografts)</i> or of different species <i>(xenografts),</i> they are usually rejected. In the 1950s, skin grafting experiments between different strains of mice demonstrated that <i>graft rejection</i> is an <a class="def" href="/books/n/mboc4/A4754/def-item/A4777/">adaptive immune response</a> to the foreign antigens on the surface of the grafted cells. Rejection is mediated mainly by T cells, which react against genetically “foreign” versions of cell-surface proteins called <i>histocompatibility molecules</i> (from the Greek word <i>histos,</i> meaning “tissue”). The MHC proteins encoded by the clustered genes of the major histocompatibility <a class="def" href="/books/n/mboc4/A4754/def-item/A5014/">complex</a> (MHC) are by far the most important of these. MHC proteins are expressed on the cells of all higher vertebrates. They were first demonstrated in mice, where they are called <i>H-2 antigens (h</i>istocompatibility-<i>2</i> antigens). In humans they are called <i>HLA antigens (h</i>uman-<i>l</i>eucocyte-<i>a</i>ssociated antigens) because they were first demonstrated on leucocytes (white blood cells).</p><p>Three remarkable properties of <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins baffled immunologists for a long time. First, MHC proteins are overwhelmingly the preferred antigens recognized in T-cell-mediated transplantation reactions. Second, an unusually large fraction of T cells are able to recognize foreign MHC proteins: whereas fewer than 0.001% of an individual's T cells respond to a typical viral <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>, more than 0.1% of them respond to a single foreign MHC antigen. Third, some of the genes that code for MHC proteins are the most <i><a class="def" href="/books/n/mboc4/A4754/def-item/A5657/">polymorphic</a></i> known in higher vertebrates. That is, within a species, there is an extraordinarily large number of <i>alleles</i> (alternative forms of the same <a class="def" href="/books/n/mboc4/A4754/def-item/A5215/">gene</a>) present (in some cases more than 200), without any one <a class="def" href="/books/n/mboc4/A4754/def-item/A4800/">allele</a> predominating. As each individual has at least 12 genes encoding MHC proteins (see later), it is very rare for two unrelated individuals to have an identical set of MHC proteins. This makes it very difficult to match donor and recipient for organ transplantation unless they are closely related.</p><p>Of course, a vertebrate does not need to protect itself against invasion by foreign vertebrate cells. So the apparent obsession of its T cells with foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins and the extreme polymorphism of these molecules were a great puzzle. The puzzle was solved only after it was discovered that (1) MHC proteins bind fragments of foreign proteins and display them on the surface of host cells for T cells to recognize, and (2) T cells respond to foreign MHC proteins in the same way they respond to self MHC proteins that have foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> bound to them.</p></div><div id="A4505"><h2 id="_A4505_">Class I and Class II MHC Proteins Are Structurally Similar Heterodimers</h2><p>Class I and class II <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins have very similar overall structures. They are both transmembrane heterodimers with extracellular N-terminal domains that bind <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> for presentation to T cells.</p><p>
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<b>Class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins</b> consist of a transmembrane α chain, which is encoded by a class I MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A5215/">gene</a>, and a small extracellular <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> called β<sub><i>2</i></sub><i>-microglobulin</i> (<a class="figpopup" href="/books/NBK26926/figure/A4506/?report=objectonly" target="object" rid-figpopup="figA4506" rid-ob="figobA4506">Figure 24-49A</a>). The β<sub>2</sub>-microglobulin does not span the <a class="def" href="/books/n/mboc4/A4754/def-item/A5438/">membrane</a> and is encoded by a gene that does not lie in the MHC gene cluster. The α chain is folded into three extracellular globular domains (α<sub>1</sub>, α<sub>2</sub>, α<sub>3</sub>), and the α<sub>3</sub> <a class="def" href="/books/n/mboc4/A4754/def-item/A5101/">domain</a> and the β<sub>2</sub>-microglobulin, which are closest to the membrane, are both similar to an <a class="def" href="/books/n/mboc4/A4754/def-item/A5313/">Ig</a> domain. The two N-terminal domains of the α chain, which are farthest from the membrane, contain the <a class="def" href="/books/n/mboc4/A4754/def-item/A5657/">polymorphic</a> (variable) amino acids that are recognized by T cells in transplantation reactions. These domains bind a peptide and present it to cytotoxic T cells.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4506" co-legend-rid="figlgndA4506"><a href="/books/NBK26926/figure/A4506/?report=objectonly" target="object" title="Figure 24-49" class="img_link icnblk_img figpopup" rid-figpopup="figA4506" rid-ob="figobA4506"><img class="small-thumb" src="/books/NBK26926/bin/ch24f49.gif" src-large="/books/NBK26926/bin/ch24f49.jpg" alt="Figure 24-49. Class I and class II MHC proteins." /></a><div class="icnblk_cntnt" id="figlgndA4506"><h4 id="A4506"><a href="/books/NBK26926/figure/A4506/?report=objectonly" target="object" rid-ob="figobA4506">Figure 24-49</a></h4><p class="float-caption no_bottom_margin">Class I and class II MHC proteins. (A) The α chain of the class I molecule has three extracellular domains, α<sub>1</sub>, α<sub>2</sub> and α<sub>3</sub>, encoded by separate exons. It is noncovalently associated with a smaller polypeptide chain, β <a href="/books/NBK26926/figure/A4506/?report=objectonly" target="object" rid-ob="figobA4506">(more...)</a></p></div></div><p>Like class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins, <b>class II MHC proteins</b>are heterodimers with two conserved <a class="def" href="/books/n/mboc4/A4754/def-item/A5313/">Ig</a>-like domains close to the <a class="def" href="/books/n/mboc4/A4754/def-item/A5438/">membrane</a> and two <a class="def" href="/books/n/mboc4/A4754/def-item/A5657/">polymorphic</a> (variable) N-terminal domains farthest from the membrane. In these proteins, however, both chains (α and β) are encoded by genes within the MHC, and both span the membrane (<a class="figpopup" href="/books/NBK26926/figure/A4506/?report=objectonly" target="object" rid-figpopup="figA4506" rid-ob="figobA4506">Figure 24-49B</a>). The two polymorphic domains bind a peptide and present it to helper T cells.</p><p>The presence of <a class="def" href="/books/n/mboc4/A4754/def-item/A5313/">Ig</a>-like domains in class I and class II proteins suggests that <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins and antibodies have a common evolutionary history. The locations of the genes that encode class I and class II MHC proteins in humans are shown in <a class="figpopup" href="/books/NBK26926/figure/A4507/?report=objectonly" target="object" rid-figpopup="figA4507" rid-ob="figobA4507">Figure 24-50</a>, where we illustrate how an individual can make six types of class I MHC proteins and more than six types of class II proteins.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4507" co-legend-rid="figlgndA4507"><a href="/books/NBK26926/figure/A4507/?report=objectonly" target="object" title="Figure 24-50" class="img_link icnblk_img figpopup" rid-figpopup="figA4507" rid-ob="figobA4507"><img class="small-thumb" src="/books/NBK26926/bin/ch24f50.gif" src-large="/books/NBK26926/bin/ch24f50.jpg" alt="Figure 24-50. Human MHC genes." /></a><div class="icnblk_cntnt" id="figlgndA4507"><h4 id="A4507"><a href="/books/NBK26926/figure/A4507/?report=objectonly" target="object" rid-ob="figobA4507">Figure 24-50</a></h4><p class="float-caption no_bottom_margin">Human MHC genes. This simplified schematic drawing shows the location of the genes that encode the transmembrane subunits of class I <i>(light green)</i> and class II <i>(dark green)</i> MHC proteins. The genes shown encode three types of class I proteins (HLA-A, HLA-B, <a href="/books/NBK26926/figure/A4507/?report=objectonly" target="object" rid-ob="figobA4507">(more...)</a></p></div></div><p>In addition to the classic class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins, there are many <i>nonclassical class I MHC proteins</i>, which form dimers with β2-microglobulin. These proteins are not <a class="def" href="/books/n/mboc4/A4754/def-item/A5657/">polymorphic</a>, but some of them present specific microbial antigens, including some lipids and glycolipids, to T cells. The functions of most of them, however, are unknown.</p></div><div id="A4508"><h2 id="_A4508_">An MHC Protein Binds a Peptide and Interacts with a T Cell Receptor</h2><p>Any individual can make only a small number of different <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins, which together must be able to present peptide fragments from almost any foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> to T cells. Thus, unlike an antibody <a class="def" href="/books/n/mboc4/A4754/def-item/A5486/">molecule</a>, each MHC protein has to be able to bind a very large number of different peptides. The structural basis for this versatility has emerged from x-ray crystallographic analyses of MHC proteins.</p><p>As shown in <a class="figpopup" href="/books/NBK26926/figure/A4509/?report=objectonly" target="object" rid-figpopup="figA4509" rid-ob="figobA4509">Figure 24-51A</a>, a class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> has a single peptide-<a class="def" href="/books/n/mboc4/A4754/def-item/A4882/">binding site</a> located at one end of the <a class="def" href="/books/n/mboc4/A4754/def-item/A5486/">molecule</a>, facing away from the <a class="def" href="/books/n/mboc4/A4754/def-item/A5642/">plasma membrane</a>. This site consists of a deep groove between two long α helices; the groove narrows at both ends so that it is only large enough to accommodate an extended peptide about 8–10 amino acids long. In fact, when a class I MHC protein was first analyzed by x-ray crystallography in 1987, this groove contained bound peptides that had co-crystallized with the MHC protein (<a class="figpopup" href="/books/NBK26926/figure/A4509/?report=objectonly" target="object" rid-figpopup="figA4509" rid-ob="figobA4509">Figure 24-51B</a>), suggesting that once a peptide binds to this site it does not normally dissociate.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4509" co-legend-rid="figlgndA4509"><a href="/books/NBK26926/figure/A4509/?report=objectonly" target="object" title="Figure 24-51" class="img_link icnblk_img figpopup" rid-figpopup="figA4509" rid-ob="figobA4509"><img class="small-thumb" src="/books/NBK26926/bin/ch24f51.gif" src-large="/books/NBK26926/bin/ch24f51.jpg" alt="Figure 24-51. The three-dimensional structure of a human class I MHC protein as determined by x-ray diffraction analysis of crystals of the extracellular part of the molecule." /></a><div class="icnblk_cntnt" id="figlgndA4509"><h4 id="A4509"><a href="/books/NBK26926/figure/A4509/?report=objectonly" target="object" rid-ob="figobA4509">Figure 24-51</a></h4><p class="float-caption no_bottom_margin">The three-dimensional structure of a human class I MHC protein as determined by x-ray diffraction analysis of crystals of the extracellular part of the molecule. The extracellular part of the protein was cleaved from the transmembrane segment by the proteolytic <a href="/books/NBK26926/figure/A4509/?report=objectonly" target="object" rid-ob="figobA4509">(more...)</a></p></div></div><p>A typical peptide binds in the groove of a class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> in an extended <a class="def" href="/books/n/mboc4/A4754/def-item/A5019/">conformation</a>, with its terminal <a class="def" href="/books/n/mboc4/A4754/def-item/A4809/">amino group</a> bound to an invariant pocket at one end of the groove and its terminal <a class="def" href="/books/n/mboc4/A4754/def-item/A4912/">carboxyl group</a> bound to an invariant pocket at the other end of the groove. Other amino acids (called “anchor amino acids”) in the peptide bind to “specificity pockets” in the groove formed by <a class="def" href="/books/n/mboc4/A4754/def-item/A5657/">polymorphic</a> portions of the MHC protein (<a class="figpopup" href="/books/NBK26926/figure/A4510/?report=objectonly" target="object" rid-figpopup="figA4510" rid-ob="figobA4510">Figure 24-52</a>). The side chains of other amino acids of the peptide point outward, in a position to be recognized by receptors on cytotoxic T cells. Because the conserved pockets at the ends of the binding groove recognize features of the peptide backbone that are common to all peptides, each allelic form of a class I MHC protein can bind a large variety of peptides of diverse sequence. At the same time, the differing specificity pockets along the groove, which bind particular <a class="def" href="/books/n/mboc4/A4754/def-item/A4807/">amino acid</a> side chains of the peptide, ensure that each allelic form binds and presents a distinct characteristic set of peptides. Thus, the six types of class I MHC proteins in an individual can present a broad range of foreign peptides to the cytotoxic T cells, but in each individual they do so in slightly different ways.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4510" co-legend-rid="figlgndA4510"><a href="/books/NBK26926/figure/A4510/?report=objectonly" target="object" title="Figure 24-52" class="img_link icnblk_img figpopup" rid-figpopup="figA4510" rid-ob="figobA4510"><img class="small-thumb" src="/books/NBK26926/bin/ch24f52.gif" src-large="/books/NBK26926/bin/ch24f52.jpg" alt="Figure 24-52. A peptide bound in the groove of a class I MHC protein." /></a><div class="icnblk_cntnt" id="figlgndA4510"><h4 id="A4510"><a href="/books/NBK26926/figure/A4510/?report=objectonly" target="object" rid-ob="figobA4510">Figure 24-52</a></h4><p class="float-caption no_bottom_margin">A peptide bound in the groove of a class I MHC protein. (A) Schematic drawing of a top view of the groove. The peptide backbone is shown as a string of <i>red</i> balls, each of which represents one of the nine amino acids of the peptide. The terminal amino <a href="/books/NBK26926/figure/A4510/?report=objectonly" target="object" rid-ob="figobA4510">(more...)</a></p></div></div><p>Class II <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins have a three-dimensional structure that is very similar to that of class I proteins, but their <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>-binding groove does not narrow at the ends, so it can accommodate longer peptides, which are usually 13–17 amino acids long. Moreover, the peptide is not bound at its ends. It is held in the groove by parts of its peptide backbone that bind to invariant pockets formed by conserved amino acids that line all class II MHC peptide-binding grooves, as well as by the side chains of anchor amino acids that bind to variable specificity pockets in the groove (<a class="figpopup" href="/books/NBK26926/figure/A4511/?report=objectonly" target="object" rid-figpopup="figA4511" rid-ob="figobA4511">Figure 24-53</a>). A class II MHC binding groove can accommodate a more heterogeneous set of peptides than can a class I MHC groove. Thus, although an individual makes only a small number of types of class II proteins, each with its own unique peptide-binding groove, together these proteins can bind and present an enormous variety of foreign peptides to helper T cells, which have a crucial role in almost all adaptive immune responses.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4511" co-legend-rid="figlgndA4511"><a href="/books/NBK26926/figure/A4511/?report=objectonly" target="object" title="Figure 24-53" class="img_link icnblk_img figpopup" rid-figpopup="figA4511" rid-ob="figobA4511"><img class="small-thumb" src="/books/NBK26926/bin/ch24f53.gif" src-large="/books/NBK26926/bin/ch24f53.jpg" alt="Figure 24-53. A peptide bound in the groove of a class II MHC protein." /></a><div class="icnblk_cntnt" id="figlgndA4511"><h4 id="A4511"><a href="/books/NBK26926/figure/A4511/?report=objectonly" target="object" rid-ob="figobA4511">Figure 24-53</a></h4><p class="float-caption no_bottom_margin">A peptide bound in the groove of a class II MHC protein. (A) Schematic drawing similar to that shown in Figure 24-52A. Note that the ends of the peptide are not tightly bound and extend beyond the cleft. The peptide is held in the groove by interactions <a href="/books/NBK26926/figure/A4511/?report=objectonly" target="object" rid-ob="figobA4511">(more...)</a></p></div></div><p>The way in which the T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> recognizes a peptide fragment bound to an <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> is revealed by x-ray crystallographic analyses of complexes formed between a soluble receptor and a soluble MHC protein with peptide in its binding groove. (The soluble proteins for these experiments are produced by <a class="def" href="/books/n/mboc4/A4754/def-item/A5723/">recombinant DNA</a> technology.) In each case studied, the T cell receptor fits diagonally across the peptide-binding groove and binds through its V<sub>α</sub> and V<sub>β</sub> hypervariable loops to both the walls of the groove and the peptide (<a class="figpopup" href="/books/NBK26926/figure/A4512/?report=objectonly" target="object" rid-figpopup="figA4512" rid-ob="figobA4512">Figure 24-54</a>). Soluble MHC-peptide complexes are now widely used to detect T cells with a particular specificity; they are usually cross-linked into tetramers to increase their <a class="def" href="/books/n/mboc4/A4754/def-item/A4861/">avidity</a> for T cell receptors.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4512" co-legend-rid="figlgndA4512"><a href="/books/NBK26926/figure/A4512/?report=objectonly" target="object" title="Figure 24-54" class="img_link icnblk_img figpopup" rid-figpopup="figA4512" rid-ob="figobA4512"><img class="small-thumb" src="/books/NBK26926/bin/ch24f54.gif" src-large="/books/NBK26926/bin/ch24f54.jpg" alt="Figure 24-54. The interaction of a T cell receptor with a viral peptide bound to a class I MHC protein." /></a><div class="icnblk_cntnt" id="figlgndA4512"><h4 id="A4512"><a href="/books/NBK26926/figure/A4512/?report=objectonly" target="object" rid-ob="figobA4512">Figure 24-54</a></h4><p class="float-caption no_bottom_margin">The interaction of a T cell receptor with a viral peptide bound to a class I MHC protein. (A) Schematic view of the hypervariable loops of the V<sub>α</sub> and V<sub>β</sub> domains of the T cell receptor interacting with the peptide and the walls of the peptide-binding <a href="/books/NBK26926/figure/A4512/?report=objectonly" target="object" rid-ob="figobA4512">(more...)</a></p></div></div></div><div id="A4513"><h2 id="_A4513_">MHC Proteins Help Direct T Cells to Their Appropriate Targets</h2><p>Class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins are expressed on virtually all nucleated cells. This is presumably because effector cytotoxic T cells must be able to focus on and kill any cell in the body that happens to become infected with an intracellular microbe such as a <a class="def" href="/books/n/mboc4/A4754/def-item/A5926/">virus</a>. Class II proteins, by contrast, are normally confined largely to cells that take up foreign antigens from the extracellular fluid and interact with helper T cells. These include dendritic cells, which initially activate helper T cells, as well as the targets of effector helper T cells, such as macrophages and B cells. Because dendritic cells express both class I and class II MHC proteins, they can activate both cytotoxic and helper T cells.</p><p>It is important that effector cytotoxic T cells focus their attack on cells that <i>make</i> the foreign antigens (such as viral proteins), while helper T cells focus their help mainly on cells that have taken up foreign antigens from the extracellular fluid. Since the former type of target cell is always a menace, while the latter type is essential for the body's immune defenses, it is vitally important that T cells never confuse the two target cells and misdirect their cytotoxic and helper functions. Therefore, in addition to the <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> that recognizes a peptide-<a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5014/">complex</a>, each of the two major classes of T cells also expresses a <i>co-receptor</i> that recognizes a separate, invariant part of the appropriate class of MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a>. These two co-receptors, called <a class="def" href="/books/n/mboc4/A4754/def-item/A4925/">CD4</a> and <a class="def" href="/books/n/mboc4/A4754/def-item/A4926/">CD8</a>, help direct helper T cells and cytotoxic T cells, respectively, to their appropriate targets, as we now discuss. The properies of class I and class II MHC proteins are compared in <a class="figpopup" href="/books/NBK26926/table/A4514/?report=objectonly" target="object" rid-figpopup="figA4514" rid-ob="figobA4514">Table 24-2</a>.</p><div class="iconblock whole_rhythm clearfix ten_col table-wrap" id="figA4514"><a href="/books/NBK26926/table/A4514/?report=objectonly" target="object" title="Table 24-2" class="img_link icnblk_img figpopup" rid-figpopup="figA4514" rid-ob="figobA4514"><img class="small-thumb" src="/books/NBK26926/table/A4514/?report=thumb" src-large="/books/NBK26926/table/A4514/?report=previmg" alt="Table 24-2. Properties of Human Class I and Class II MHC Proteins." /></a><div class="icnblk_cntnt"><h4 id="A4514"><a href="/books/NBK26926/table/A4514/?report=objectonly" target="object" rid-ob="figobA4514">Table 24-2</a></h4><p class="float-caption no_bottom_margin">Properties of Human Class I and Class II MHC Proteins. </p></div></div></div><div id="A4515"><h2 id="_A4515_">CD4 and CD8 Co-receptors Bind to Nonvariable Parts of MHC Proteins</h2><p>The affinity of T cell receptors for peptide-<a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> complexes on an <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> or target cell is usually too low to mediate a functional interaction between the two cells by itself. T cells normally require <i>accessory receptors</i> to help stabilize the interaction by increasing the overall strength of the cell-cell adhesion. Unlike T cell receptors or MHC proteins, the accessory receptors do not bind foreign antigens and are invariant.</p><p>When accessory receptors also have a direct role in activating the T cell by generating their own intracellular signals, they are called <b>co-receptors</b>. The most important and best understood of the co-receptors on T cells are the <a class="def" href="/books/n/mboc4/A4754/def-item/A4925/">CD4</a> and <a class="def" href="/books/n/mboc4/A4754/def-item/A4926/">CD8</a> proteins, both of which are single-pass transmembrane proteins with extracellular <a class="def" href="/books/n/mboc4/A4754/def-item/A5313/">Ig</a>-like domains. Like T cell receptors, they recognize <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins, but, unlike T cell receptors, they bind to nonvariable parts of the <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a>, far away from the peptide-binding groove. <a href="/books/n/mboc4/A4754/#A4925">CD4</a> is expressed on helper T cells and binds to class II MHC proteins, whereas <a href="/books/n/mboc4/A4754/#A4926">CD8</a> is expressed on cytotoxic T cells and binds to class I MHC proteins (<a class="figpopup" href="/books/NBK26926/figure/A4516/?report=objectonly" target="object" rid-figpopup="figA4516" rid-ob="figobA4516">Figure 24-55</a>). Thus, CD4 and CD8 contribute to T cell recognition by helping to focus the cell on particular MHC proteins, and thus on particular types of cells—helper T cells on dendritic cells, macrophages, and B cells, and cytotoxic cells on any nucleated host cell displaying a foreign peptide on a class I MHC protein. The cytoplasmic tail of these transmembrane proteins is associated with a member of the <a class="def" href="/books/n/mboc4/A4754/def-item/A5824/">Src family</a> of cytoplasmic tyrosine protein kinases called <i>Lck</i>, which phosphorylates various intracellular proteins on tyrosines and thereby participates in the activation of the T cell. Antibodies to CD4 and CD8 are widely used as tools to distinguish between the two main classes of T cells, in both humans and experimental animals.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4516" co-legend-rid="figlgndA4516"><a href="/books/NBK26926/figure/A4516/?report=objectonly" target="object" title="Figure 24-55" class="img_link icnblk_img figpopup" rid-figpopup="figA4516" rid-ob="figobA4516"><img class="small-thumb" src="/books/NBK26926/bin/ch24f55.gif" src-large="/books/NBK26926/bin/ch24f55.jpg" alt="Figure 24-55. CD4 and CD8 co-receptors on the surface of T cells." /></a><div class="icnblk_cntnt" id="figlgndA4516"><h4 id="A4516"><a href="/books/NBK26926/figure/A4516/?report=objectonly" target="object" rid-ob="figobA4516">Figure 24-55</a></h4><p class="float-caption no_bottom_margin">CD4 and CD8 co-receptors on the surface of T cells. Cytotoxic T cells (T<sub>C</sub>) express CD8, which recognizes class I MHC proteins, whereas helper T cells (T<sub>H</sub>) express CD4, which recognizes class II MHC proteins. Note that the co-receptors bind to the same <a href="/books/NBK26926/figure/A4516/?report=objectonly" target="object" rid-ob="figobA4516">(more...)</a></p></div></div><p>Ironically, the AIDS <a class="def" href="/books/n/mboc4/A4754/def-item/A5926/">virus</a> (<a class="def" href="/books/n/mboc4/A4754/def-item/A5284/">HIV</a>) makes use of <a class="def" href="/books/n/mboc4/A4754/def-item/A4925/">CD4</a> molecules (as well as <a class="def" href="/books/n/mboc4/A4754/def-item/A4965/">chemokine</a> receptors) to enter helper T cells. It is the eventual depletion of helper T cells that renders AIDS patients susceptible to infection by microbes that are not normally dangerous. As a result, most AIDS patients die of infection within several years of the onset of symptoms, unless they are treated with a combination of powerful anti-HIV drugs. HIV also uses CD4 and chemokine receptors to enter macrophages, which also have both of these receptors on their surface.</p><p>Before a cytotoxic or <a class="def" href="/books/n/mboc4/A4754/def-item/A5269/">helper T cell</a> can recognize a foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a>, the protein has to be processed inside an <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> or target cell so that it can be displayed as peptide-<a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> complexes on the cell surface. We first consider how a <a class="def" href="/books/n/mboc4/A4754/def-item/A5926/">virus</a>-infected antigen-presenting cell or target cell processes viral proteins for presentation to a <a class="def" href="/books/n/mboc4/A4754/def-item/A5056/">cytotoxic T cell</a>. We then discuss how ingested foreign proteins are processed for presentation to a helper T cell.</p></div><div id="A4517"><h2 id="_A4517_">Cytotoxic T Cells Recognize Fragments of Foreign Cytosolic Proteins in Association with Class I MHC Proteins</h2><p>One of the first, and most dramatic, demonstrations that <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins present foreign antigens to T cells came from an experiment performed in the 1970s. It was found that effector cytotoxic T cells from a <a class="def" href="/books/n/mboc4/A4754/def-item/A5926/">virus</a>-infected mouse could kill cultured cells infected with the same virus only if these target cells expressed some of the same class I MHC proteins as the infected mouse (<a class="figpopup" href="/books/NBK26926/figure/A4518/?report=objectonly" target="object" rid-figpopup="figA4518" rid-ob="figobA4518">Figure 24-56</a>). This experiment demonstrated that the T cells of any individual that recognize a specific <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> do so only when that antigen is associated with the allelic forms of MHC proteins expressed by that individual, a phenomenon known as <i>MHC restriction.</i>
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4518" co-legend-rid="figlgndA4518"><a href="/books/NBK26926/figure/A4518/?report=objectonly" target="object" title="Figure 24-56" class="img_link icnblk_img figpopup" rid-figpopup="figA4518" rid-ob="figobA4518"><img class="small-thumb" src="/books/NBK26926/bin/ch24f56.gif" src-large="/books/NBK26926/bin/ch24f56.jpg" alt="Figure 24-56. The classic experiment showing that an effector cytotoxic T cell recognizes some aspect of the surface of the host target cell in addition to a viral antigen." /></a><div class="icnblk_cntnt" id="figlgndA4518"><h4 id="A4518"><a href="/books/NBK26926/figure/A4518/?report=objectonly" target="object" rid-ob="figobA4518">Figure 24-56</a></h4><p class="float-caption no_bottom_margin">The classic experiment showing that an effector cytotoxic T cell recognizes some aspect of the surface of the host target cell in addition to a viral antigen. Mice of strain X are infected with virus A. Seven days later, the spleens of these mice contain <a href="/books/NBK26926/figure/A4518/?report=objectonly" target="object" rid-ob="figobA4518">(more...)</a></p></div></div><p>The chemical nature of the viral antigens recognized by cytotoxic T cells was not discovered for another 10 years. In experiments on cells infected with influenza <a class="def" href="/books/n/mboc4/A4754/def-item/A5926/">virus</a>, it was unexpectedly found that some of the effector cytotoxic T cells activated by the virus specifically recognize internal proteins of the virus that would not be accessible in the intact virus particle. Subsequent evidence indicated that the T cells were recognizing degraded fragments of the internal viral proteins that were bound to class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins on the infected cell surface. Because a T cell can recognize tiny amounts of <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> (as few as one hundred peptide-MHC complexes), only a small fraction of the fragments generated from viral proteins have to bind to class I MHC proteins and get to the cell surface to attract an attack by an effector <a class="def" href="/books/n/mboc4/A4754/def-item/A5056/">cytotoxic T cell</a>.</p><p>The viral proteins are synthesized in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5055/">cytosol</a> of the infected cell. As discussed in Chapter 3, proteolytic degradation in the cytosol is mainly mediated by an ATP- and <a class="def" href="/books/n/mboc4/A4754/def-item/A5910/">ubiquitin</a>-dependent mechanism that operates in <i>proteasomes</i>—large <a class="def" href="/books/n/mboc4/A4754/def-item/A5699/">proteolytic enzyme</a> complexes constructed from many different <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> subunits. Although all proteasomes are probably able to generate peptide fragments that can bind to class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins, some proteasomes are thought to be specialized for this purpose, as they contain two subunits that are encoded by genes located within the MHC chromosomal region. Even bacterial proteasomes cut proteins into peptides of about the length that fits into the groove of a class I MHC protein, suggesting that the MHC groove evolved to fit this length of peptide.</p><p>How do peptides generated in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5055/">cytosol</a> make contact with the peptide-binding groove of class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5409/">lumen</a> of the <a class="def" href="/books/n/mboc4/A4754/def-item/A5131/">endoplasmic reticulum</a> (<a class="figpopup" href="/books/NBK26926/figure/A4519/?report=objectonly" target="object" rid-figpopup="figA4519" rid-ob="figobA4519">Figure 24-57</a>)? The answer was discovered through observations on <a class="def" href="/books/n/mboc4/A4754/def-item/A5500/">mutant</a> cells in which class I MHC proteins are not expressed at the cell surface but are instead degraded within the cell. The mutant genes in these cells proved to encode subunits of a <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> belonging to the family of <i>ABC transporters,</i> which we discuss in Chapter 11. This transporter protein is located in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5151/">ER</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5438/">membrane</a> and uses the energy of ATP hydrolysis to <a class="def" href="/books/n/mboc4/A4754/def-item/A5708/">pump</a> peptides from the cytosol into the <a class="def" href="/books/n/mboc4/A4754/def-item/A5147/">ER lumen</a>. The genes encoding its two subunits are in the MHC chromosomal region, and, if either <a class="def" href="/books/n/mboc4/A4754/def-item/A5215/">gene</a> is inactivated by <a class="def" href="/books/n/mboc4/A4754/def-item/A5502/">mutation</a>, cells are unable to supply peptides to class I MHC proteins. The class I MHC proteins in such mutant cells are degraded in the cell because peptide binding is normally required for the proper folding of these proteins. Until it binds a peptide, a class I MHC protein remains in the ER, tethered to an ABC transporter by a chaperone protein (<a class="figpopup" href="/books/NBK26926/figure/A4520/?report=objectonly" target="object" rid-figpopup="figA4520" rid-ob="figobA4520">Figure 24-58</a>).
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4519" co-legend-rid="figlgndA4519"><a href="/books/NBK26926/figure/A4519/?report=objectonly" target="object" title="Figure 24-57" class="img_link icnblk_img figpopup" rid-figpopup="figA4519" rid-ob="figobA4519"><img class="small-thumb" src="/books/NBK26926/bin/ch24f57.gif" src-large="/books/NBK26926/bin/ch24f57.jpg" alt="Figure 24-57. The peptide-transport problem." /></a><div class="icnblk_cntnt" id="figlgndA4519"><h4 id="A4519"><a href="/books/NBK26926/figure/A4519/?report=objectonly" target="object" rid-ob="figobA4519">Figure 24-57</a></h4><p class="float-caption no_bottom_margin">The peptide-transport problem. How do peptide fragments get from the cytosol, where they are produced, into the ER lumen, where the peptide-binding grooves of class I MHC proteins are located? A special transport process is required. </p></div></div><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4520" co-legend-rid="figlgndA4520"><a href="/books/NBK26926/figure/A4520/?report=objectonly" target="object" title="Figure 24-58" class="img_link icnblk_img figpopup" rid-figpopup="figA4520" rid-ob="figobA4520"><img class="small-thumb" src="/books/NBK26926/bin/ch24f58.gif" src-large="/books/NBK26926/bin/ch24f58.jpg" alt="Figure 24-58. The processing of a viral protein for presentation to cytotoxic T cells." /></a><div class="icnblk_cntnt" id="figlgndA4520"><h4 id="A4520"><a href="/books/NBK26926/figure/A4520/?report=objectonly" target="object" rid-ob="figobA4520">Figure 24-58</a></h4><p class="float-caption no_bottom_margin">The processing of a viral protein for presentation to cytotoxic T cells. An effector cytotoxic T cell kills a virus-infected cell when it recognizes fragments of viral protein bound to class I MHC proteins on the surface of the infected cell. Not all <a href="/books/NBK26926/figure/A4520/?report=objectonly" target="object" rid-ob="figobA4520">(more...)</a></p></div></div><p>In cells that are not infected, peptide fragments come from the cells' own cytosolic and nuclear proteins that are degraded in the processes of normal <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> turnover and quality control mechanisms. (Surprisingly, more than 30% of the proteins made by mammalian cells are apparently faulty and are degraded in proteasomes soon after they are synthesized.) These peptides are pumped into the <a class="def" href="/books/n/mboc4/A4754/def-item/A5131/">ER</a> and are carried to the cell surface by class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins. They are not antigenic because the cytotoxic T cells that could recognize them have been eliminated or inactivated during T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5071/">development</a>, as we discuss later.</p><p>When cytotoxic T cells and some helper T cells are activated by <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> to become effector cells, they secrete the <a class="def" href="/books/n/mboc4/A4754/def-item/A5050/">cytokine</a> <b>interferon-γ (IFN-γ)</b>, which greatly enhances anti-viral responses. The IFN-γ acts on infected cells in two ways. It blocks viral replication, and it increases the <a class="def" href="/books/n/mboc4/A4754/def-item/A5163/">expression</a> of many genes within the <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> chromosomal region. These genes include those that encode class I (and class II) MHC proteins, the two specialized <a class="def" href="/books/n/mboc4/A4754/def-item/A5687/">proteasome</a> subunits, and the two subunits of the peptide transporter located in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5131/">ER</a> (<a class="figpopup" href="/books/NBK26926/figure/A4521/?report=objectonly" target="object" rid-figpopup="figA4521" rid-ob="figobA4521">Figure 24-59</a>). Thus, all of the machinery required for presenting viral antigens to cytotoxic T cells is coordinately called into action by IFN-γ, creating a positive feedback that amplifies the <a class="def" href="/books/n/mboc4/A4754/def-item/A5319/">immune response</a> and culminates in the death of the infected cells.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4521" co-legend-rid="figlgndA4521"><a href="/books/NBK26926/figure/A4521/?report=objectonly" target="object" title="Figure 24-59" class="img_link icnblk_img figpopup" rid-figpopup="figA4521" rid-ob="figobA4521"><img class="small-thumb" src="/books/NBK26926/bin/ch24f59.gif" src-large="/books/NBK26926/bin/ch24f59.jpg" alt="Figure 24-59. Some effects of interferon-γ on infected cells." /></a><div class="icnblk_cntnt" id="figlgndA4521"><h4 id="A4521"><a href="/books/NBK26926/figure/A4521/?report=objectonly" target="object" rid-ob="figobA4521">Figure 24-59</a></h4><p class="float-caption no_bottom_margin">Some effects of interferon-γ on infected cells. The activated interferon-γ receptors signal to the nucleus, altering gene transcription, which leads to the effects indicated. The effects shaded in <i>yellow</i> tend to make the infected cell <a href="/books/NBK26926/figure/A4521/?report=objectonly" target="object" rid-ob="figobA4521">(more...)</a></p></div></div></div><div id="A4522"><h2 id="_A4522_">Helper T Cells Recognize Fragments of Endocytosed Foreign Protein Associated with Class II MHC Proteins</h2><p>Unlike cytotoxic T cells, helper T cells do not act directly to kill infected cells so as to eliminate microbes. Instead, they stimulate macrophages to be more effective in destroying intracellular microorganisms, and they help B cells and cytotoxic T cells to respond to microbial antigens.</p><p>Like the viral proteins presented to cytotoxic T cells, the proteins presented to helper T cells on <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>-presenting cells or target cells are degraded fragments of foreign proteins. The fragments are bound to class II <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins in much the same way that <a class="def" href="/books/n/mboc4/A4754/def-item/A5926/">virus</a>-derived peptides are bound to class I MHC proteins. But both the source of the peptide fragments presented and the route they take to find the MHC proteins are different from those of peptide fragments presented by class I MHC proteins to cytotoxic T cells.</p><p>Rather than being derived from foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> synthesized in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5055/">cytosol</a> of a cell, the foreign peptides presented to helper T cells are derived from endosomes. Some come from extracellular microbes or their products that the <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> has endocytosed and degraded in the acidic environment of its endosomes. Others come from microbes growing within the endocytic <a class="def" href="/books/n/mboc4/A4754/def-item/A5009/">compartment</a> of the antigen-presenting cell. These peptides do not have to be pumped across a <a class="def" href="/books/n/mboc4/A4754/def-item/A5438/">membrane</a> because they do not originate in the cytosol; they are generated in a compartment that is topologically equivalent to the extracellular space. They never enter the <a class="def" href="/books/n/mboc4/A4754/def-item/A5409/">lumen</a> of the <a class="def" href="/books/n/mboc4/A4754/def-item/A5131/">ER</a>, where the class II <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins are synthesized and assembled, but instead bind to preassembled class II heterodimers in a special endosomal compartment. Once the peptide has bound, the class II MHC protein alters its <a class="def" href="/books/n/mboc4/A4754/def-item/A5019/">conformation</a>, trapping the peptide in the binding groove for presentation at the cell surface to helper T cells.</p><p>A newly synthesized class II <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> must avoid clogging its binding groove prematurely in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5147/">ER lumen</a> with peptides derived from endogenously synthesized proteins. A special <a class="def" href="/books/n/mboc4/A4754/def-item/A5658/">polypeptide</a>, called the <b>invariant chain</b>, ensures this by associating with newly synthesized class II MHC heterodimers in the ER. Part of its polypeptide chain lies within the peptide-binding groove of the MHC protein, thereby blocking the groove from binding other peptides in the lumen of the ER. The invariant chain also directs class II MHC proteins from the <i>trans</i> Golgi network to a late endosomal <a class="def" href="/books/n/mboc4/A4754/def-item/A5009/">compartment</a>. Here, the invariant chain is cleaved by proteases, leaving only a short fragment bound in the peptide-binding groove of the MHC protein. This fragment is then released (catalyzed by a class II-MHC-like protein called HLA-DM), freeing the MHC protein to bind peptides derived from endocytosed proteins (<a class="figpopup" href="/books/NBK26926/figure/A4523/?report=objectonly" target="object" rid-figpopup="figA4523" rid-ob="figobA4523">Figure 24-60</a>). In this way, the functional differences between class I and class II MHC proteins are ensured—the former presenting molecules that come from the <a class="def" href="/books/n/mboc4/A4754/def-item/A5055/">cytosol</a>, the latter presenting molecules that come from the endocytic compartment.
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4523" co-legend-rid="figlgndA4523"><a href="/books/NBK26926/figure/A4523/?report=objectonly" target="object" title="Figure 24-60" class="img_link icnblk_img figpopup" rid-figpopup="figA4523" rid-ob="figobA4523"><img class="small-thumb" src="/books/NBK26926/bin/ch24f60.gif" src-large="/books/NBK26926/bin/ch24f60.jpg" alt="Figure 24-60. The processing of an extracellular protein antigen for presentation to a helper T cell." /></a><div class="icnblk_cntnt" id="figlgndA4523"><h4 id="A4523"><a href="/books/NBK26926/figure/A4523/?report=objectonly" target="object" rid-ob="figobA4523">Figure 24-60</a></h4><p class="float-caption no_bottom_margin">The processing of an extracellular protein antigen for presentation to a helper T cell. The drawing shows a simplified view of how peptide-class-II-MHC complexes are formed in endosomes and delivered to the cell surface. Note that the release of the invariant-chain <a href="/books/NBK26926/figure/A4523/?report=objectonly" target="object" rid-ob="figobA4523">(more...)</a></p></div></div><p>Most of the class I and class II <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins on the surface of a target cell have peptides derived from self proteins in their binding groove. For class I proteins, the fragments derive from degraded cytosolic and nuclear proteins. For class II proteins, they mainly derive from degraded proteins that originate in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5642/">plasma membrane</a> or extracellular fluid and are endocytosed. Only a small fraction of the 10<sup>5</sup> or so class II MHC proteins on the surface of an <a class="def" href="/books/n/mboc4/A4754/def-item/A4833/">antigen-presenting cell</a> have foreign peptides bound to them. This is sufficient, however, because only a hundred or so of such molecules are required to stimulate a <a class="def" href="/books/n/mboc4/A4754/def-item/A5269/">helper T cell</a>, just as in the case of peptide-class-I-MHC complexes stimulating a <a class="def" href="/books/n/mboc4/A4754/def-item/A5056/">cytotoxic T cell</a>.</p></div><div id="A4524"><h2 id="_A4524_">Potentially Useful T Cells Are Positively Selected in the Thymus</h2><p>We have seen that T cells recognize <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> in association with self <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins but not in association with foreign MHC proteins (see <a class="figpopup" href="/books/NBK26926/figure/A4518/?report=objectonly" target="object" rid-figpopup="figA4518" rid-ob="figobA4518">Figure 24-56</a>): that is, T cells show <i>MHC restriction.</i> This restriction results from a process of <b>positive selection</b> during T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5071/">development</a> in the thymus. In this process, those immature T cells that will be capable of recognizing foreign peptides presented by self MHC proteins are selected to survive, while the remainder, which would be of no use to the animal, undergo <a class="def" href="/books/n/mboc4/A4754/def-item/A4839/">apoptosis</a>. Thus, MHC restriction is an acquired property of the <a class="def" href="/books/n/mboc4/A4754/def-item/A5320/">immune system</a> that emerges as T cells develop in the thymus.</p><p>The most direct way to study the selection process is to follow the fate of a set of developing T cells of known specificity. This can be done by using transgenic mice that express a specific pair of rearranged α and β T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> genes derived from a T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A4994/">clone</a> of known <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> and <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> specificity. Such experiments show that the transgenic T cells mature in the thymus and populate the peripheral lymphoid organs only if the transgenic mouse also expresses the same allelic form of MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> as is recognized by the transgenic T cell receptor. If the mouse does not express the appropriate MHC protein, the transgenic T cells die in the thymus. Thus, the survival and maturation of a T cell depend on a match between its receptor and the MHC proteins expressed in the thymus. Similar experiments using transgenic mice in which MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A5163/">expression</a> is confined to specific cell types in the thymus indicate that it is MHC proteins on epithelial cells in the cortex of the thymus that are responsible for this positive selection process. After positively selected T cells leave the thymus, their continued survival depends on their continual stimulation by self-peptide-MHC complexes; this stimulation is enough to promote cell survival but not enough to activate the T cells to become effector cells.</p><p>As part of the positive selection process in the thymus, developing T cells that express receptors recognizing class I <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins are selected to become cytotoxic cells, while T cells that express receptors recognizing class II MHC proteins are selected to become helper cells. Thus, genetically engineered mice that lack cell-surface class I MHC proteins specifically lack cytotoxic T cells, whereas mice that lack class II MHC proteins specifically lack helper T cells. The cells that are undergoing positive selection initially express both <a class="def" href="/books/n/mboc4/A4754/def-item/A4925/">CD4</a> and <a class="def" href="/books/n/mboc4/A4754/def-item/A4926/">CD8</a> co-receptors, and these are required for the selection process: without CD4, helper T cells fail to develop, and without CD8, cytotoxic T cells fail to develop.</p><p>Positive selection still leaves a large problem to be solved. If developing T cells with receptors that recognize self peptides associated with self <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins were to mature in the thymus and migrate to peripheral lymphoid tissues, they might wreak havoc. A second, <i>negative selection</i> process in the thymus is required to help avoid this potential disaster.</p></div><div id="A4525"><h2 id="_A4525_">Many Developing T Cells That Could Be Activated by Self Peptides Are Eliminated in the Thymus</h2><p>As discussed previously, a fundamental feature of the adaptive <a class="def" href="/books/n/mboc4/A4754/def-item/A5320/">immune system</a> is that it can distinguish self from nonself and normally does not react against self molecules. An important mechanism in achieving this state of <i>immunological self tolerance</i> is the <a class="def" href="/books/n/mboc4/A4754/def-item/A5062/">deletion</a> in the thymus of developing self-reactive T cells—that is, T cells whose receptors bind strongly enough to the <a class="def" href="/books/n/mboc4/A4754/def-item/A5014/">complex</a> of a self peptide and a self <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> to become activated. Because, as we discuss later, most B cells require helper T cells to respond to <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>, the elimination of self-reactive helper T cells also helps ensure that self-reactive B cells that escape B cell tolerance <a class="def" href="/books/n/mboc4/A4754/def-item/A5329/">induction</a> are harmless.</p><p>It is not enough, therefore, for the thymus to select <i>for</i> T cells that recognize self <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins; it must also select <i>against</i> T cells that could be activated by self MHC proteins complexed with self peptides. In other words, it must pick out for survival just those T cells that will be capable of responding to self MHC proteins complexed with foreign peptides, even though these peptides are not present in the developing thymus. It is thought that these T cells bind weakly in the thymus to self MHC proteins that are carrying self peptides mismatched to the T cell receptors. Thus, the required goal can be achieved by (1) ensuring the death of T cells that bind <i>strongly</i> to the self-peptide-MHC complexes in the thymus while (2) promoting the survival of those that bind weakly and (3) permitting the death of those that do not bind at all. Process 2 is the positive selection we have just discussed. Process 1 is called <b>negative selection</b>. In both death processes, the cells that die undergo <a class="def" href="/books/n/mboc4/A4754/def-item/A4839/">apoptosis</a> (<a class="figpopup" href="/books/NBK26926/figure/A4526/?report=objectonly" target="object" rid-figpopup="figA4526" rid-ob="figobA4526">Figure 24-61</a>).
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</p><div class="iconblock whole_rhythm clearfix ten_col fig" id="figA4526" co-legend-rid="figlgndA4526"><a href="/books/NBK26926/figure/A4526/?report=objectonly" target="object" title="Figure 24-61" class="img_link icnblk_img figpopup" rid-figpopup="figA4526" rid-ob="figobA4526"><img class="small-thumb" src="/books/NBK26926/bin/ch24f61.gif" src-large="/books/NBK26926/bin/ch24f61.jpg" alt="Figure 24-61. Positive and negative selection in the thymus." /></a><div class="icnblk_cntnt" id="figlgndA4526"><h4 id="A4526"><a href="/books/NBK26926/figure/A4526/?report=objectonly" target="object" rid-ob="figobA4526">Figure 24-61</a></h4><p class="float-caption no_bottom_margin">Positive and negative selection in the thymus. Cells with receptors that would enable them to respond to foreign peptides in association with self MHC proteins survive, mature, and migrate to peripheral lymphoid organs. All of the other cells undergo <a href="/books/NBK26926/figure/A4526/?report=objectonly" target="object" rid-ob="figobA4526">(more...)</a></p></div></div><p>The most convincing evidence for negative selection derives once again from experiments with transgenic mice. After the introduction of T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> transgenes encoding a receptor that recognizes a male-specific peptide <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>, for example, large numbers of mature T cells expressing the transgenic receptor are found in the thymus and peripheral lymphoid organs of female mice. Very few, however, are found in male mice, where the cells die in the thymus before they have a chance to mature. Like positive selection, negative selection requires the interaction of a T cell receptor and a <a class="def" href="/books/n/mboc4/A4754/def-item/A4925/">CD4</a> or <a class="def" href="/books/n/mboc4/A4754/def-item/A4926/">CD8</a> co-receptor with an appropriate <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a>. Unlike positive selection, however, which occurs mainly on the surface of thymus epithelial cells, negative selection occurs on the surface of thymus dendritic cells and macrophages, which, as we have seen, function as antigen-presenting cells in peripheral lymphoid organs.</p><p>The <a class="def" href="/books/n/mboc4/A4754/def-item/A5062/">deletion</a> of self-reactive T cells in the thymus cannot eliminate all potentially self-reactive T cells, as some self molecules are not present in the thymus. Thus, some potentially self-reactive T cells are deleted or functionally inactivated after they leave the thymus, presumably because they recognize self peptides bound to <a class="def" href="/books/n/mboc4/A4754/def-item/A5421/">MHC</a> proteins on the surface of dendritic cells that have not been activated by microbes and therefore do not provide a costimulatory signal. As we discuss later, <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> recognition without costimulatory signals can delete or inactivate a T or B cell.</p><p>Some potentially self-reactive T cells, however, are not deleted or inactivated. Instead, special <i>regulatory</i> (or <i>suppressor) T cells</i> are thought to keep them from responding to their self antigens by secreting inhibitory cytokines such as TGF-β (discussed in Chapter 15). These self-reactive T cells may sometimes escape from this suppression and cause autoimmune diseases.</p></div><div id="A4527"><h2 id="_A4527_">The Function of MHC Proteins Explains Their Polymorphism</h2><p>The role of <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins in binding foreign peptides and presenting them to T cells provides an explanation for the extensive polymorphism of these proteins. In the evolutionary war between pathogenic microbes and the adaptive <a class="def" href="/books/n/mboc4/A4754/def-item/A5320/">immune system</a>, microbes tend to change their antigens to avoid associating with MHC proteins. When a microbe succeeds, it is able to sweep through a population as an epidemic. In such circumstances, the few individuals that produce a new MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> that can associate with an <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a> of the altered microbe have a large selective advantage. In addition, individuals with two different alleles at any given MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A5405/">locus</a> (heterozygotes) have a better chance of resisting infection than those with identical alleles at the locus, as they have a greater capacity to present peptides from a wide range of microbes and parasites. Thus, selection will tend to promote and maintain a large diversity of MHC proteins in the population. Strong support for this hypothesis, that infectious diseases have provided the driving force for MHC polymorphism, has come from studies in West Africa. Here, it is found that individuals with a specific MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A4800/">allele</a> have a reduced susceptibility to a severe form of <a class="def" href="/books/n/mboc4/A4754/def-item/A5422/">malaria</a>. Although the allele is rare elsewhere, it is found in 25% of the West African population where this form of malaria is common.</p><p>If greater <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> diversity means greater resistance to infection, why do we each have so few MHC genes encoding these molecules? Why have we not evolved strategies for increasing the diversity of MHC proteins—by <a class="def" href="/books/n/mboc4/A4754/def-item/A4804/">alternative RNA splicing</a>, for example, or by the <a class="def" href="/books/n/mboc4/A4754/def-item/A5220/">genetic recombination</a> mechanisms used to diversify antibodies and T cell receptors? Presumably, the limits exist because each time a new MHC <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> is added to the repertoire, the T cells that recognize self peptides in association with the new MHC protein must be eliminated to maintain self tolerance. The elimination of these T cells would counteract the advantage of adding the new MHC protein. Thus, the number of MHC proteins we express may represent a balance between the advantages of presenting a wide diversity of foreign peptides to T cells against the disadvantages of severely restricting the T cell repertoire during negative selection in the thymus. This explanation is supported by computer modeling studies.</p></div><div id="A4528"><h2 id="_A4528_">Summary</h2><p>There are two main functionally distinct classes of T cells: cytotoxic T cells kill infected cells directly by inducing them to undergo <a class="def" href="/books/n/mboc4/A4754/def-item/A4839/">apoptosis</a>, while helper T cells help activate B cells to make antibody responses and macrophages to destroy microorganisms that either invaded the <a class="def" href="/books/n/mboc4/A4754/def-item/A5420/">macrophage</a> or were ingested by it. Helper T cells also help activate cytotoxic T cells. Both classes of T cells express cell-surface, antibodylike receptors, which are encoded by genes that are assembled from multiple <a class="def" href="/books/n/mboc4/A4754/def-item/A5215/">gene</a> segments during T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5071/">development</a> in the thymus. These receptors recognize fragments of foreign proteins that are displayed on the surface of host cells in association with <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins. Both cytotoxic and helper T cells are activated in peripheral lymphoid organs by <a class="def" href="/books/n/mboc4/A4754/def-item/A4830/">antigen</a>-presenting cells, which express peptide-MHC complexes, costimulatory proteins, and various cell-cell adhesion molecules on their cell surface.</p><p>Class I and class II <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins have crucial roles in presenting foreign <a class="def" href="/books/n/mboc4/A4754/def-item/A5688/">protein</a> antigens to cytotoxic and helper T cells, respectively. Whereas class I proteins are expressed on almost all vertebrate cells, class II proteins are normally restricted to those cell types that interact with helper T cells, such as dendritic cells, macrophages, and B lymphocytes. Both classes of MHC proteins have a single peptide-binding groove, which binds small peptide fragments derived from proteins. Each MHC protein can bind a large and characteristic set of peptides, which are produced intracellularly by protein degradation: class I MHC proteins generally bind fragments produced in the <a class="def" href="/books/n/mboc4/A4754/def-item/A5055/">cytosol</a>, while class II MHC proteins bind fragments produced in the endocytic <a class="def" href="/books/n/mboc4/A4754/def-item/A5009/">compartment</a>. After they have formed inside the target cell, the peptide-MHC complexes are transported to the cell surface. Complexes that contain a peptide derived from a foreign protein are recognized by T cell receptors, which interact with both the peptide and the walls of the peptide-binding groove. T cells also express <a class="def" href="/books/n/mboc4/A4754/def-item/A4925/">CD4</a> or <a class="def" href="/books/n/mboc4/A4754/def-item/A4926/">CD8</a> co-receptors, which recognize nonpolymorphic regions of MHC proteins on the target cell: helper cells express CD4, which recognizes class II MHC proteins, while cytotoxic T cells express CD8, which recognizes class I MHC proteins.</p><p>The T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5720/">receptor</a> repertoire is shaped mainly by a combination of positive and negative selection processes that operate during T cell <a class="def" href="/books/n/mboc4/A4754/def-item/A5071/">development</a> in the thymus. These processes help to ensure that only T cells with potentially useful receptors survive and mature, while the others die by <a class="def" href="/books/n/mboc4/A4754/def-item/A4839/">apoptosis</a>. T cells that will be able to respond to foreign peptides complexed with self <a class="def" href="/books/n/mboc4/A4754/def-item/A5456/">MHC</a> proteins are positively selected, while many T cells that could react strongly with self peptides complexed with self MHC proteins are eliminated. T cells with receptors that could react strongly with self antigens not present in the thymus are eliminated, functionally inactivated, or actively kept suppressed after they leave the thymus.</p></div><div style="display:none"><div id="figA4427"><img alt="Image ch24f5" src-large="/books/n/mboc4/A4422/bin/ch24f5.jpg" /></div><div id="figA3105"><img alt="Image ch16f97" src-large="/books/n/mboc4/A3082/bin/ch16f97.jpg" /></div><div id="figA4681"><img alt="Image ch25f42" src-large="/books/n/mboc4/A4674/bin/ch25f42.jpg" /></div><div id="figA4473"><img alt="Image ch24f34" src-large="/books/n/mboc4/A4446/bin/ch24f34.jpg" /></div></div></div></div>
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<div class="post-content"><div><p>By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.</p><div class="half_rhythm"><a href="/books/about/copyright/">Copyright</a> © 2002, Bruce Alberts, Alexander Johnson, Julian
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Lewis, Martin Raff, Keith Roberts, and Peter Walter; Copyright © 1983,
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1989, 1994, Bruce Alberts, Dennis Bray, Julian Lewis, Martin Raff, Keith Roberts,
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and James D. Watson .</div><div class="small"><span class="label">Bookshelf ID: NBK26926</span></div></div></div>
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<div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance"></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Views</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="PDF_download" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a data-jig="ncbidialog" href="#_ncbi_dlg_citbx_NBK26926" data-jigconfig="width:400,modal:true">Cite this Page</a><div id="_ncbi_dlg_citbx_NBK26926" style="display:none" title="Cite this Page"><div class="bk_tt">Alberts B, Johnson A, Lewis J, et al. Molecular Biology of the Cell. 4th edition. New York: Garland Science; 2002. T Cells and MHC Proteins.<span class="bk_cite_avail"></span></div></div></li><li><a href="#" class="toggle-glossary-link" title="Enable/disable links to the glossary">Disable Glossary Links</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>In this Page</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="page-toc" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="#A4492" ref="log$=inpage&link_id=inpage">T Cell Receptors Are Antibodylike Heterodimers</a></li><li><a href="#A4494" ref="log$=inpage&link_id=inpage">Antigen-Presenting Cells Activate T Cells</a></li><li><a href="#A4497" ref="log$=inpage&link_id=inpage">Effector Cytotoxic T Cells Induce Infected Target Cells to Kill Themselves</a></li><li><a href="#A4500" ref="log$=inpage&link_id=inpage">Effector Helper T Cells Help Activate Macrophages, B Cells, and Cytotoxic T Cells</a></li><li><a href="#A4502" ref="log$=inpage&link_id=inpage">T Cells Recognize Foreign Peptides Bound to MHC Proteins</a></li><li><a href="#A4504" ref="log$=inpage&link_id=inpage">MHC Proteins Were Identified in Transplantation Reactions Before Their Functions Were Known</a></li><li><a href="#A4505" ref="log$=inpage&link_id=inpage">Class I and Class II MHC Proteins Are Structurally Similar Heterodimers</a></li><li><a href="#A4508" ref="log$=inpage&link_id=inpage">An MHC Protein Binds a Peptide and Interacts with a T Cell Receptor</a></li><li><a href="#A4513" ref="log$=inpage&link_id=inpage">MHC Proteins Help Direct T Cells to Their Appropriate Targets</a></li><li><a href="#A4515" ref="log$=inpage&link_id=inpage">CD4 and CD8 Co-receptors Bind to Nonvariable Parts of MHC Proteins</a></li><li><a href="#A4517" ref="log$=inpage&link_id=inpage">Cytotoxic T Cells Recognize Fragments of Foreign Cytosolic Proteins in Association with Class I MHC Proteins</a></li><li><a href="#A4522" ref="log$=inpage&link_id=inpage">Helper T Cells Recognize Fragments of Endocytosed Foreign Protein Associated with Class II MHC Proteins</a></li><li><a href="#A4524" ref="log$=inpage&link_id=inpage">Potentially Useful T Cells Are Positively Selected in the Thymus</a></li><li><a href="#A4525" ref="log$=inpage&link_id=inpage">Many Developing T Cells That Could Be Activated by Self Peptides Are Eliminated in the Thymus</a></li><li><a href="#A4527" ref="log$=inpage&link_id=inpage">The Function of MHC Proteins Explains Their Polymorphism</a></li><li><a href="#A4528" ref="log$=inpage&link_id=inpage">Summary</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Related Items in Bookshelf</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="source-links" id="Shutter"></a></div><div class="portlet_content"><ul xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="simple-list"><li><a href="https://www.ncbi.nlm.nih.gov/books?term="textbooks"%5BResource%20Type%5D" ref="pagearea=source-links&targetsite=external&targetcat=link&targettype=uri">All Textbooks</a></li></ul></div></div><div class="portlet"><div class="portlet_head"><div class="portlet_title"><h3><span>Recent Activity</span></h3></div><a name="Shutter" sid="1" href="#" class="portlet_shutter" title="Show/hide content" remembercollapsed="true" pgsec_name="recent_activity" id="Shutter"></a></div><div class="portlet_content"><div xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" id="HTDisplay" class=""><div class="action"><a href="javascript:historyDisplayState('ClearHT')">Clear</a><a href="javascript:historyDisplayState('HTOff')" class="HTOn">Turn Off</a><a href="javascript:historyDisplayState('HTOn')" class="HTOff">Turn On</a></div><ul id="activity"><li class="ra_rcd ralinkpopper two_line"><a class="htb ralinkpopperctrl" ref="log$=activity&linkpos=1" href="/portal/utils/pageresolver.fcgi?recordid=67d6a3b7cde49f3df7bea682">Genetic Information in Eucaryotes - 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