Alternative titles; symbols
HGNC Approved Gene Symbol: KLRG1
Cytogenetic location: 12p13.31 Genomic coordinates (GRCh38) : 12:8,950,044-9,215,570 (from NCBI)
Inhibitory lectin-like receptors, including KLRG1, are expressed on the surface of hematopoietic cells and regulate immunocyte effector functions through interactions with specific ligands. For example, major histocompatibility complex (MHC) class I molecules are recognized by natural killer (NK) cells. All of these inhibitory receptors contain a cytoplasmic immunoreceptor tyrosine-based inhibitory motif, or ITIM. Upon MHC I engagement and tyrosine phosphorylation of the ITIM, intracellular tyrosine protein phosphatases such as SHP1 (PTPN6; 176883) are recruited to the ITIM, and an inhibitory signal cascade leads to the abrogation of NK cell activation (summary by Hanke et al., 1998).
By searching an EST database for sequences similar to the ITIM-bearing rat mast cell function-associated antigen (MAFA), Butcher et al. (1998) and Hanke et al. (1998) identified clones encoding KLRG1, which Butcher et al. (1998) designated MAFAL. Using PCR analysis on a basophil-like leukemia cell line and human lung mast cells, Lamers et al. (1998) also isolated a cDNA encoding KLRG1, which they called MAFA. The deduced 189-amino acid KLRG1 is a type II transmembrane protein containing a C-type lectin carbohydrate recognition domain, an intracellular ITIM-like motif, and 4 potential N-glycosylation sites. Northern blot analysis by Butcher et al. (1998) detected a 1-kb KLRG1 transcript in spleen, lymph node, and peripheral blood leukocytes. By RT-PCR analysis, Butcher et al. (1998) found expression of KLRG1 in peripheral blood NK cells, a monocytic cell line, and a basophilic leukemia cell line; expression was not found in decidual NK cells, B cells, and T cells.
Through comparison with the rat MAFA sequence, Lamers et al. (1998) determined that the human KLRG1 gene contains 5 exons. They showed that 2 alternatively spliced variants exist, one lacking exon 3 (E3-negative) and the other lacking exons 3 and 4 (E3/4-negative). E3-negative KLRG1 was predicted to have a short extracellular region and was expressed in lung mast cells, basophils, and a basophilic leukemia cell line. The E3/4-negative variant was expressed only in a basophilic leukemia cell line.
Voehringer et al. (2001) determined that the mouse Klrg1 gene spans 13 kb and contains 5 exons.
By PCR analysis of radiation hybrid panels and YACs, Butcher et al. (1998) mapped the single-copy KLRG1 gene to the telomeric side of the NK cell gene complex on chromosome 12p13-p12.
Voehringer et al. (2001) mapped the Klrg1 gene to mouse chromosome 6, outside the NK complex, between the CD9 (143030) and CD4 (186940) genes.
Crystal Structure
Cadherins are downregulated in metastatic tumors. By determining the crystal structure of KLRG1 in complex with E-cadherin (CDH1; 192090) at 2.0-angstrom resolution, Li et al. (2009) determined that KLRG1 mediated missing self recognition by binding to a highly conserved site on cadherins, enabling monitoring of expression of CDH1, CDH2 (114020), and CDH4 (603006) on target cells. Li et al. (2009) proposed that CDH1 may coengage KLRG1 and integrin alpha-E (ITGAE; 604682)/beta-7 (ITGB7; 147559) and that KLRG1 overcomes its weak affinity for cadherins through multipoint attachment to target cells, resulting in inhibitory signaling.
Grundemann et al. (2006) identified E-cadherin as a ligand for mouse Klrg1. Ectopic expression of E-cadherin by melanoma target cells did not affect cytolytic activity of NK cells, but it inhibited antigen-induced cell division and cytolytic activity of effector CD8 (186910)-positive T cells.
Banh et al. (2009) showed that the first 2 extracellular domains of N-cadherin (CDH2) interacted with KLRG1, blocked interaction of KLRG1 with E-cadherin, and could regulate KLRG1 signaling. Binding of KLRG1 to E-cadherin inhibited E-cadherin-dependent cell adhesion and led to tyrosine phosphorylation of E-cadherin. The KLRG1/E-cadherin interaction led to the generation of a bidirectional signal in which both KLRG1 and E-cadherin activated downstream signaling cascades simultaneously, regulating cells expressing one or the other molecule.
Using a reporter system in mice, Herndler-Brandstetter et al. (2018) found that, following infection with Listeria monocytogenes, Klrg1-positive Cd8-positive effector T cells downregulated Klrg1 expression in a Bach2 (605394)-dependent manner and differentiated into long-lived circulating and tissue-resident 'exKLRG1' memory T cells. Genomewide transcriptional profiling showed that exKLRG1 memory T cells were heterogeneous and consisted of all memory T-cell lineages. ExKLRG1 memory T cells retained high cytotoxic and proliferative capacities distinct from other populations and were able to provide anti-influenza and antitumor immunity.
Banh, C., Fugere, C., Brossay, L. Immunoregulatory functions of KLRG1 cadherin interactions are dependent on forward and reverse signaling. Blood 114: 5299-5306, 2009. [PubMed: 19855082] [Full Text: https://doi.org/10.1182/blood-2009-06-228353]
Butcher, S., Arney, K. L., Cook, G. P. MAFA-L, an ITIM-containing receptor encoded by the human NK cell gene complex and expressed by basophils and NK cells. Europ. J. Immun. 28: 3755-3762, 1998. [PubMed: 9842918] [Full Text: https://doi.org/10.1002/(SICI)1521-4141(199811)28:11<3755::AID-IMMU3755>3.0.CO;2-3]
Grundemann, C., Bauer, M., Schweier, O., von Oppen, N., Lassing, U., Saudan, P., Becker, K.-F., Karp, K., Hanke, T., Bachmann, M. F., Pircher, H. Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. J. Immun. 176: 1311-1315, 2006. [PubMed: 16424155] [Full Text: https://doi.org/10.4049/jimmunol.176.3.1311]
Hanke, T., Corral, L., Vance, R. E., Raulet, D. H. 2F1 antigen, the mouse homolog of the rat 'mast cell function-associated antigen', is a lectin-like type II transmembrane receptor expressed by natural killer cells. Europ. J. Immun. 28: 4409-4417, 1998. [PubMed: 9862378] [Full Text: https://doi.org/10.1002/(SICI)1521-4141(199812)28:12<4409::AID-IMMU4409>3.0.CO;2-3]
Herndler-Brandstetter, D., Ishigame, H., Shinnakasu, R., Plajer, V., Stecher, C., Zhao, J., Lietzenmayer, M., Kroehling, L., Takumi, A., Kometani, K., Inoue, T., Kluger, Y., Kaech, S. M., Kurosaki, T., Okada, T, Flavell, R. A. KLRG1+ effector CD8+ T cells lose KLRG1, differentiate into all memory T cell lineages, and convey enhanced protective immunity. Immunity 48: 716-729, 2018. [PubMed: 29625895] [Full Text: https://doi.org/10.1016/j.immuni.2018.03.015]
Lamers, M. B. A. C., Lamont, A. G., Williams, D. H. Human MAFA has alternatively spliced variants. Biochim. Biophys. Acta 1399: 209-212, 1998. [PubMed: 9765598] [Full Text: https://doi.org/10.1016/s0167-4781(98)00107-9]
Li, Y., Hofmann, M., Wang, Q., Teng, L., Chlewicki, L. K., Pircher, H., Mariuzza, R. A. Structure of natural killer cell receptor KLRG1 bound to E-cadherin reveals basis for MHC-independent missing self recognition. Immunity 31: 35-46, 2009. [PubMed: 19604491] [Full Text: https://doi.org/10.1016/j.immuni.2009.04.019]
Voehringer, D., Kaufmann, M., Pircher, H. Genomic structure, alternative splicing, and physical mapping of the killer cell lectin-like receptor G1 gene (KLRG1), the mouse homologue of MAFA. Immunogenetics 52: 206-211, 2001. [PubMed: 11220622] [Full Text: https://doi.org/10.1007/s002510000282]