Alternative titles; symbols
HGNC Approved Gene Symbol: LY9
Cytogenetic location: 1q23.3 Genomic coordinates (GRCh38): 1:160,796,174-160,828,255 (from NCBI)
LY9 belongs to the SLAM family of immunomodulatory receptors (see SLAMF1; 603492) and interacts with the adaptor molecule SAP (SH2D1A; 300490) (Graham et al., 2006).
By sequence analysis of cDNA clones, Sandrin et al. (1992) demonstrated that the mouse lymphocyte surface antigen Ly9 is a novel member of a subgroup of the immunoglobulin superfamily, together with the antigens CD2 (186990), BCM1 (CD48; 109530), and LFA3 (CD58; 153420). Kingsmore et al. (1995) noted that, though the function of Ly9 was unknown, other subgroup members are involved in adhesion reactions between T lymphocytes and accessory cells. CD2, CD48, and CD58 are also distinguished by homophilic interactions with one another; thus, human CD48 and CD58 are both ligands for CD2.
Kingsmore et al. (1995) noted that genetic and physical mapping studies have suggested that the Ig subgroup containing LY9, CD2, CD48, and CD58 may have arisen through duplication of a chromosomal segment. CD2 and CD58 are located less than 250 kb apart, close to the ATP1A1 gene (182310) on the proximal short arm of human chromosome 1. The locus for CD48 is adjacent to a related gene, ATP1A2 (182340), and is also on human chromosome 1, but on the proximal long arm, a considerable distance from CD2, CD58, and ATP1A1. Mouse Cd2 and Cd48, while located on different autosomes, are also adjacent to the respective NaK-ATPase homologs, Atp1a1 and Atp1a2. The mouse Ly9 gene was mapped by strain serologic differences to the same region of mouse chromosome 1 as Cd48 and Atp1a2 (Kozak et al., 1984). Kingsmore et al. (1995) showed that the gene encoding Ly9 is located adjacent to CD48 and the Na,K-ATPase alpha-2 subunit gene on human and mouse chromosome 1. Mapping of the mouse gene was performed using a panel of DNA samples from an interspecific backcross and by physical mapping by pulsed field gel electrophoresis. This placed Ly9 within 1,100 kb of Cd48 and Atp1a2. The human homolog, LY9, was physically mapped by pulsed field gel electrophoresis indicating that LY9 is located within 410 kb of CD48, which had been assigned to 1q21.3-q22. The location of 6 genes, 2 clusters of 3 genes each, may be explained by the occurrence of 2 successive duplication events during vertebrate evolution and suggests that Ly9 may also participate in adhesion reactions between T lymphocytes and accessory cells by homophilic interaction.
Using flow cytometric analysis, Hagberg et al. (2013) found that stimulating peripheral blood mononuclear cells with RNA-containing immune complexes (RNA-ICs) resulted in increased expression of the SLAM family members CD229 and CD319 (SLAMF7; 606625) on plasmacytoid dendritic cells (pDCs) and of CD319 on natural killer (NK) cells. Upregulation of CD229 and CD319 on RNA-IC-stimulated pDCs was induced by NK cells or cytokines, such as GMCSF (CSF2; 138960) and IL3 (147740). IFNA (147660)-producing pDCs displayed higher SLAM molecule expression than IFNA-negative pDCs. The authors found that pDCs expressed the downstream signaling molecules SHIP1 (INPP5D; 601582), SHP1 (PTPN6; 176883), SHP2 (PTPN11; 176876), and CSK (124095), but lacked SAP (300490) and EAT2 (SH2D1B; 608510), suggesting that CD229 and CD319 act as inhibitory receptors on pDCs. Patients with systemic lupus erythematosus (SLE; 152700) showed decreased CD319 expression on pDCs and decreased CD229 expression on NK cells, and RNA-IC stimulation increased expression of both. Hagberg et al. (2013) concluded that expression of CD229 and CD319 is regulated on pDCs and NK cells by lupus immune complexes and that expression of these receptors is specifically altered in SLE.
Using surface plasmon resonance, Margraf et al. (2015) showed that the val602 variant of the nonsynonymous SNP rs509749 in CD229 had 2-fold lower affinity for SAP compared with the met602 variant. The val602 variant was more highly expressed in human T-cell lines than the met602 variant and was associated with diminished activation response, as measured by upregulation of CD69 (107273). Margraf et al. (2015) proposed that SNPs like rs509749 may perturb fine-tuning in the immune system.
By targeting exon 2 of Ly9, Graham et al. (2006) generated viable, fertile Ly9-deficient mice. In contrast to mice deficient in Slam or Sap, T lymphocyte proliferation and Il2 (147680) production were poor in Ly9-deficient mice. Il4 (147780) production was only somewhat reduced in Ly9-deficient mice. Unlike Slam-deficient macrophages, Ly9-deficient macrophages exhibited no defects in cytokine production or bacterial killing. Unlike Sap-deficient mice, Ly9-deficient mice had no defects in natural killer T-cell development and had appropriate T- and B-cell responses to lymphocytic choriomeningitis virus. Graham et al. (2006) concluded that, like other SLAM family members, LY9 has a role in promoting Th2 polarization, but it is also critical in enhancing T-cell activation.
Graham, D. B., Bell, M. P., McCausland, M. M., Huntoon, C. J., van Deursen, J., Faubion, W. A., Crotty, S., McKean, D. J. Ly9 (CD229)-deficient mice exhibit T cell defects yet do not share several phenotypic characteristics associated with SLAM- and SAP-deficient mice. J. Immun. 176: 291-300, 2006. Note: Erratum: J Immun. 176: 3841 only, 2006. [PubMed: 16365421] [Full Text: https://doi.org/10.4049/jimmunol.176.1.291]
Hagberg, N., Theorell, J., Schlums, H., Eloranta, M.-L., Bryceson, Y. T., Ronnblom, L. Systemic lupus erythematosus immune complexes increase the expression of SLAM family members CD319 (CRACC) and CD229 (LY-9) on plasmacytoid dendritic cells and CD319 on CD56-dim NK cells. J. Immun. 191: 2989-2998, 2013. [PubMed: 23956418] [Full Text: https://doi.org/10.4049/jimmunol.1301022]
Kingsmore, S. F., Souryal, C. A., Watson, M. L., Patel, D. D., Seldin, M. F. Physical and genetic linkage of the genes encoding Ly-9 and CD48 on mouse and human chromosomes 1. Immunogenetics 42: 59-62, 1995. [PubMed: 7797269] [Full Text: https://doi.org/10.1007/BF00164988]
Kozak, C. A., Davidson, W. F., Morse, H. C., III. Genetic and functional relationships of the retroviral and lymphocyte alloantigen loci on mouse chromosome 1. Immunogenetics 19: 163-168, 1984. [PubMed: 6321340] [Full Text: https://doi.org/10.1007/BF00387860]
Margraf, S., Garner, L. I., Wilson, T. J., Brown, M. H. A polymorphism in a phosphotyrosine signalling motif of CD229 (Ly9, SLAMF3) alters SH2 domain binding and T-cell activation. Immunology 146: 392-400, 2015. [PubMed: 26221972] [Full Text: https://doi.org/10.1111/imm.12513]
Sandrin, M. S., Gumley, T. P., Henning, M. M., Vaughan, H. A., Gonez, L. J., Trapani, J. A., McKenzie, I. F. C. Isolation and characterization of cDNA clones for mouse Ly-9. J. Immun. 149: 1636-1641, 1992. [PubMed: 1506686]