Alternative titles; symbols
HGNC Approved Gene Symbol: SLAMF6
Cytogenetic location: 1q23.2-q23.3 Genomic coordinates (GRCh38): 1:160,485,036-160,523,255 (from NCBI)
By immunologic and functional analyses, Bottino et al. (2001) identified a 60-kD tyrosine-phosphorylated antigen involved in the lysis of Epstein-Barr virus-infected cells. The antigen was expressed on natural killer (NK), T, and B lymphocytes and was therefore termed NTBA. By immunoscreening an NK cell-derived cDNA expression library, Bottino et al. (2001) isolated a cDNA, which they termed KALI, encoding NTBA. The deduced 332-amino acid type I transmembrane NTBA protein is a member of the immunoglobulin superfamily. It has a leader peptide; 7 potential N-linked glycosylation sites in its 204-residue extracellular region; a 23-amino acid transmembrane region lacking charged residues; and an 83-amino acid intracytoplasmic portion containing 2 TxYxxV/I motifs, which are thought to interact with SH2D1A (300490), and an immunoreceptor tyrosine-based inhibitory motif (ITIM). RT-PCR analysis detected expression of an allelic isoform of NTBA, which the authors called KALIb, that has an insertion of an alanine residue at position 266 of the mature protein.
Natural cytotoxicity receptors, such as NKp46 (604530), NKp44 (604531), and NKp30 (NCR3; 611550), are selectively expressed on NK cells and cooperate in the induction of NK cell activity. Optimal triggering may also depend on interactions between 2B4 (605554) and its ligand, CD48 (109530). Interactions of 2B4 with mutant SH2D1A in patients with X-linked lymphoproliferative disease (XLPD; 308240) results in a sharp inhibition rather than activation of NK cells. Bottino et al. (2001) found that triggering of NK cells via NTBA required the simultaneous engagement of NKp46. Similar to 2B4, NTBA mediated inhibitory signals in NK cells from XLP patients. Binding analysis showed no association with LAT (602354) but interaction with SHP1 (PTPN6; 176883) and, upon tyrosine phosphorylation, SH2D1A and SHP2 (PTPN11; 176876).
Using trimeric recombinant proteins, Flaig et al. (2004) showed that NTBA is its own ligand. Their findings indicated that homophilic interaction of NTBA enhances NK-cell activity and may increase IFNG (147570) production in the presence of other ligands. Flaig et al. (2004) proposed that NTBA is an interlymphocytic signaling molecule involved in orchestrating the activities of immune cells.
Kumar et al. (2006) noted that the z allele of Sle1 and its component sublocus Sle1b (see 601744), derived from a lupus-prone mouse strain, are linked to a variety of lupus-related disease phenotypes, including antinuclear antibodies, splenomegaly, and glomerulonephritis. SLAM gene family members are located within the Sle1bz sublocus and have been linked to murine spontaneous lupus. Analysis of mice expressing Sle1z/Sle1bz showed impaired B-cell anergy, receptor revision, and deletion. Among SLAM family members, the Ly108.1 isoform of Ly108 was most highly expressed in immature B cells from lupus-prone Sle1z mice. The normal allele, Ly108.2, but not Ly108.1, sensitized immature B cells to deletion and Rag (see 179615) reexpression. Kumar et al. (2006) concluded that some of the genes causing murine lupus may function by crippling multiple B-cell tolerance mechanisms. They suggested that Ly108 isoforms may function as molecular rheostats, determining the stringency with which self-reactive B cells are censored during early development.
By studying T-cell receptor (TCR; see 186740) restimulation of preactivated T cells from Epstein-Barr virus-naive XLP patients after prolonged exposure to IL2 (147680), Snow et al. (2009) found that activated T cells from these patients were specifically and substantially less sensitive to restimulation-induced cell death (RICD). Silencing SAP (SH2D1A) or NTBA expression recapitulated resistance to RICD in normal T cells, indicating that both molecules are necessary for optimal TCR-induced apoptosis. TCR restimulation triggered increased recruitment of SAP to NTBA, and these proteins functioned to augment TCR-induced signal strength and induction of downstream proapoptotic target genes, including FASL (TNFSF6; 134638) and BIM (BCL2L11; 603827).
Crystal Structure
Cao et al. (2006) obtained the 3-angstrom crystal structure of the human NTBA ectodomain. The structure revealed a rod-like monomer that self-associates to form a highly kinked dimer.
By Southern blot analysis, Bottino et al. (2001) mapped the NTBA gene to chromosome 1, where all the other CD2 (186990) subfamily members are localized.
Howie et al. (2005) generated mice with a targeted disruption of exons 2 and 3 of the Ly108 gene. RT-PCR detected only a residual transcript encoding the transmembrane and cytoplasmic domains of Ly108 in these mice. ELISA showed that mitogen-stimulated Cd4 (186940)-positive T cells from mutant mice produced significantly less Il4 (147780) than cells from wildtype mice. T cells from mutant mice infected with Leishmania mexicana parasites exhibited decreased Il4 production, and these mice had delayed lesion formation. Infection with Salmonella typhimurium or an attenuated mutant showed that mutant mice had defective neutrophils that produced increased Il12b (161561), Tnf (191160), and Il6 (147620) and displayed poor bactericidal activity. Macrophage functions appeared normal in mutant mice. Howie et al. (2005) concluded that LY108 has a critical role in CD4-positive T-cell responses and innate immunity to parasites and bacteria.
Bottino, C., Falco, M., Parolini, S., Marcenaro, E., Augugliaro, R., Sivori, S., Landi, E., Biassoni, R., Notarangelo, L. D., Moretta, L., Moretta, A. NTB-A, a novel SH2D1A-associated surface molecule contributing to the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked lymphoproliferative disease. J. Exp. Med. 194: 235-246, 2001. Note: Erratum: J. Exp. Med. 194: 705 only, 2001. [PubMed: 11489943] [Full Text: https://doi.org/10.1084/jem.194.3.235]
Cao, E., Ramagopal, U. A., Fedorov, A., Federov, E., Yan, Q., Lary, J. W., Cole, J. L., Nathenson, S. G., Almo, S. C. NTB-A receptor crystal structure: insights into homophilic interactions in the signaling lymphocytic activation molecule receptor family. Immunity 25: 559-570, 2006. [PubMed: 17045824] [Full Text: https://doi.org/10.1016/j.immuni.2006.06.020]
Flaig, R. M., Stark, S., Watzl, C. Cutting edge: NTB-A activates NK cells via homophilic interaction. J. Immun. 172: 6524-6527, 2004. [PubMed: 15153464] [Full Text: https://doi.org/10.4049/jimmunol.172.11.6524]
Howie, D., Laroux, F. S., Morra, M., Satoskar, A. R., Rosas, L. E., Faubion, W. A., Julien, A., Rietdijk, S., Coyle, A. J., Fraser, C., Terhorst, C. Cutting edge: the SLAM family receptor Ly108 controls T cell and neutrophil functions. J. Immun. 174: 5931-5935, 2005. [PubMed: 15879084] [Full Text: https://doi.org/10.4049/jimmunol.174.10.5931]
Kumar, K. R., Li, L., Yan, M., Bhaskarabhatla, M., Mobley, A. B., Nguyen, C., Mooney, J. M., Schatzle, J. D., Wakeland, E. K., Mohan, C. Regulation of B cell tolerance by the lupus susceptibility gene Ly108. Science 312: 1665-1669, 2006. [PubMed: 16778059] [Full Text: https://doi.org/10.1126/science.1125893]
Snow, A. L., Marsh, R. A., Krummey, S. M., Roehrs, P., Young, L. R., Zhang, K., van Hoff, J., Dhar, D., Nichols, K. E., Filipovich, A. H., Su, H. C., Bleesing, J. J., Lenardo, M. J. Restimulation-induced apoptosis of T cells is impaired in patients with X-linked lymphoproliferative disease caused by SAP deficiency. J. Clin. Invest. 119: 2976-2989, 2009. [PubMed: 19759517] [Full Text: https://doi.org/10.1172/JCI39518]