Alternative titles; symbols
HGNC Approved Gene Symbol: CD6
Cytogenetic location: 11q12.2 Genomic coordinates (GRCh38): 11:60,971,680-61,020,377 (from NCBI)
CD6 is a monomeric 105- or 130-kD membrane glycoprotein that is involved in T-cell activation. The size difference between the 2 CD6 forms is due to differences in phosphorylation (Robinson et al., 1995).
Tsuge et al. (1985) recognized a T-cell antigen with a molecular mass of 120 kD, Tp120, by means of a monoclonal antibody. The antigen was expressed on all T cells.
By screening a human peripheral blood acute lymphocytic leukemia cell cDNA expression library with antibodies against CD6, Aruffo et al. (1991) cloned a cDNA encoding CD6. The predicted 468-amino acid protein contains a 24-amino acid signal sequence, 3 extracellular 'scavenger receptor cysteine-rich' (SRCR) domains (see CD5L; 602592), a membrane-spanning domain, and a 44-amino acid cytoplasmic domain (see Robinson et al., 1995). It shows significant homology to CD5 (153340). By Northern blot analysis, CD6 is expressed as an approximately 3-kb mRNA in T cells.
Robinson et al. (1995) cloned a mouse Cd6 cDNA by screening a thymus cDNA library with a human CD6 cDNA. The predicted 665-amino acid mouse protein has a 243-amino acid cytoplasmic domain. By Northern blot analysis, mouse Cd6 was expressed predominantly in thymus, lymph node, and spleen. The authors noted that human CD6 is expressed predominantly in peripheral T cells and mature medullary thymocytes.
Due to the apparent size discrepancy between the cytoplasmic domains of human CD6 (44 amino acids; Aruffo et al., 1991) and mouse Cd6 (243 amino acids; Robinson et al., 1995), Robinson et al. (1995) used RT-PCR on human peripheral blood lymphocyte mRNA to isolate cDNA clones that include the C-terminal coding region of human CD6. A hybrid cDNA consisting of the 5-prime sequence isolated by Aruffo et al. (1991) and the longest 3-prime sequence isolated by the authors encodes a predicted 668-amino acid protein containing an additional 200 amino acids in the cytoplasmic domain. Antibodies against CD6 immunoprecipitated monomeric 105- and 130-kD proteins from cells expressing the hybrid cDNA; these 2 proteins comigrated with endogenous CD6 immunoprecipitated in parallel experiments. Robinson et al. (1995) noted that immunoprecipitation of endogenous CD6 did not reveal a smaller protein corresponding to the size of the predicted CD6 protein containing the 44-amino acid cytoplasmic domain. The authors identified 2 additional cDNAs lacking sequences encoding membrane-proximal regions of the cytoplasmic domain and suggested that the shorter cDNAs represent alternatively spliced CD6 transcripts.
Bowen et al. (1997) confirmed that the sequence of the CD6 cDNA isolated by Aruffo et al. (1991) arose via alternative splicing, and they identified additional mRNAs resulting from variable splicing of exons encoding the cytoplasmic domain. By Northern blot analysis, these alternatively spliced transcripts were not very abundant.
By immunoprecipitation analysis using a CD6 fusion protein, Joo et al. (2000) identified 2 CD6 ligands, CD166 (ALCAM; 601662) and 3A11, on epithelial and mesenchymal cells. Using FACS analysis, Saifullah et al. (2004) showed that both CD166 and 3A11 were expressed at different levels on a variety of epithelial and mesenchymal cell lines derived from thymus, skin, synovium, and cartilage. Expression of 3A11, but not CD166, was enhanced by IFNG (147570). Based on these and other findings, Saifullah et al. (2004) concluded that 3A11 and CD166 are distinct CD6 ligands.
Using mass spectroscopy, proteomics, and immunoblot analysis, Enyindah-Asonye et al. (2017) determined that monoclonal antibody 3A11 recognized CD318 (CDCP1; 611735). Pull-down analysis confirmed that soluble CD6 bound CD318. Further analysis and flow cytometry with wildtype and CD166-deficient cells showed that CD6 interacted with both CD318 and CD166. CD318 was expressed on synovial fibroblasts and endothelial cells and was secreted into synovial fluid, but not serum, of patients with rheumatoid arthritis (RA; 180300) or juvenile inflammatory arthritis (see 604302), but not osteoarthritis (OA; see 165720). CD318 was involved in recruitment and retention of T cells in synovial tissue. Treatment of synovial fibroblasts with IFNG resulted in adhesion of T cells not only to CD166, but also to CD318. Mice lacking Cd318 had reduced central nervous system injury and pathogenic T-cell infiltration compared with wildtype mice following induction of experimental autoimmune encephalomyelitis. Enyindah-Asonye et al. (2017) concluded that CD318 is a ligand for CD6 and that this interaction is important in autoimmune disease.
Bowen et al. (1997) reported that the CD6 gene contains at least 13 exons and spans more than 25 kb.
From the study of human-mouse somatic cell hybrids, Tsuge et al. (1985) showed a correlation between chromosome 11 and expression of Tp120. The presence of human chromosome 11 was confirmed by the isozyme analysis of LDHA (150000).
Bowen et al. (1997) mapped the CD6 gene to a YAC contig at 11q13, as determined by fluorescence in situ hybridization. The CD6 gene is located close to the related gene CD5, leading Bowen et al. (1997) to suggest that these genes arose from a common ancestral gene. Lecomte et al. (1996) found that the mouse Cd6 and Cd5 genes are located in a tandem array less than 55 kb apart on the proximal end of chromosome 19, a region showing homology of synteny with human 11q.
In a metaanalysis of genomewide association studies including 2,624 patients with multiple sclerosis (MS; 126200) and 7,220 controls, followed by replication in an independent set of 2,215 patients with MS and 2,116 controls, De Jager et al. (2009) identified several novel loci for MS susceptibility, including chromosome 11q13 (rs17824933) in the CD6 gene (p = 3.79 x 10(-9)).
By RT-PCR and functional analyses, Kofler et al. (2011) showed that the MS risk allele (G) of rs17824933 in intron 1 of the CD6 gene was associated with decreased expression of full-length CD6 in CD4 (186940)-positive and CD8 (see 186910)-positive T cells. Consequently, proliferation was diminished during long-term activation of CD4-positive T cells from individuals with the risk allele. Knockdown of full-length CD6 with exon 5-specific small interfering RNA induced a similar defect in individuals homozygous for the protective allele (C). CD4-positive T cells from individuals with the risk allele exhibited consistent underexpression of CD6 exon 5, which encodes the ALCAM-binding site in the protein. Kofler et al. (2011) concluded that the MS risk allele of rs17824933 is associated with altered proliferation of CD4-positive T cells.
Aruffo, A., Melnick, M. B., Linsley, P. S., Seed, B. The lymphocyte glycoprotein CD6 contains a repeated domain structure characteristic of a new family of cell surface and secreted proteins. J. Exp. Med. 174: 949-952, 1991. [PubMed: 1919444] [Full Text: https://doi.org/10.1084/jem.174.4.949]
Bowen, M. A., Whitney, G. S., Neubauer, M., Starling, G. C., Palmer, D., Zhang, J., Nowak, N. J., Shows, T. B., Aruffo, A. Structure and chromosomal location of the human CD6 gene. J. Immun. 158: 1149-1156, 1997. [PubMed: 9013954]
De Jager, P. L., Jia, X., Wang, J., de Bakker, P. I. W., Ottoboni, L., Aggarwal, N. T., Picco, L., Raychaudhuri, S., Tran, D., Aubin, C., Briskin, R., Romano, S., and 22 others. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci. Nature Genet. 41: 776-782, 2009. [PubMed: 19525953] [Full Text: https://doi.org/10.1038/ng.401]
Enyindah-Asonye, G., Li, Y., Ruth, J. H., Spassov, D. S., Hebron, K. E., Zijlstra, A., Moasser, M. M., Wang, B., Singer, N. G., Cui, H., Ohara, R. A., Rasmussen, S. M., Fox, D. A., Lin, F. CD318 is a ligand for CD6. Proc. Nat. Acad. Sci. 114: E6912-E6921, 2017. [PubMed: 28760953] [Full Text: https://doi.org/10.1073/pnas.1704008114]
Joo, Y.-S., Singer, N. G., Endres, J. L., Sarkar, S., Kinne, R. W., Marks, R. M., Fox, D. A. Evidence for the expression of a second CD6 ligand by synovial fibroblasts. Arthritis Rheum. 43: 329-335, 2000. [PubMed: 10693872] [Full Text: https://doi.org/10.1002/1529-0131(200002)43:2<329::AID-ANR12>3.0.CO;2-Y]
Kofler, D. M., Severson, C. A., Mousissian, N., De Jager, P. L., Hafler, D. A. The CD6 multiple sclerosis susceptibility allele is associated with alterations in CD4+ T cell proliferation. J. Immun. 187: 3286-3291, 2011. [PubMed: 21849685] [Full Text: https://doi.org/10.4049/jimmunol.1100626]
Lecomte, O., Bock, J. B., Birren, B. W., Vollrath, D., Parnes, J. R. Molecular linkage of the mouse CD5 and CD6 genes. Immunogenetics 44: 385-390, 1996. [PubMed: 8781125] [Full Text: https://doi.org/10.1007/BF02602784]
Robinson, W. H., Neuman de Vegvar, H. E., Prohaska, S. S., Rhee, J. W., Parnes, J. R. Human CD6 possesses a large, alternatively spliced cytoplasmic domain. Europ. J. Immun. 25: 2765-2769, 1995. [PubMed: 7589069] [Full Text: https://doi.org/10.1002/eji.1830251008]
Robinson, W. H., Prohaska, S. S., Santoro, J. C., Robinson, H. L., Parnes, J. R. Identification of a mouse protein homologous to the human CD6 T cell surface protein and sequence of the corresponding cDNA. J. Immun. 155: 4739-4748, 1995. [PubMed: 7594475]
Saifullah, M. K., Fox, D. A., Sarkar, S., Abidi, S. M. A., Endres, J., Piktel, J., Haqqi, T. M., Singer, N. G. Expression and characterization of a novel CD6 ligand in cells derived from joint and epithelial tissues. J. Immun. 173: 6125-6133, 2004. [PubMed: 15528349] [Full Text: https://doi.org/10.4049/jimmunol.173.10.6125]
Tsuge, I., Utsumi, K. R., Ueda, R., Takamoto, S., Takahashi, T. Assignment of gene coding human T-cell differentiation antigen, Tp120, to chromosome 11. Somat. Cell Molec. Genet. 11: 217-222, 1985. [PubMed: 3923629] [Full Text: https://doi.org/10.1007/BF01534678]