The CD6 multiple sclerosis susceptibility allele is associated with alterations in CD4+ T cell proliferation

• Published in: The Journal of immunology (1950) 2011-09, Vol.187 (6), p.3286-3291
• Main Authors: Kofler, David M, Severson, Christopher A, Mousissian, Narine, De Jager, Philip L, Hafler, David A
• Format: Article
• Language: English
• Subjects: Alleles; Antigens, CD - genetics; Antigens, CD - immunology; Antigens, Differentiation, T-Lymphocyte - genetics; Antigens, Differentiation, T-Lymphocyte - immunology; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - cytology; Cell Proliferation; Cell Separation; Cells, Cultured; Female; Flow Cytometry; Genetic Predisposition to Disease; Genotype; Humans; Male; Multiple Sclerosis - genetics; Multiple Sclerosis - immunology; Phenotype; Reverse Transcriptase Polymerase Chain Reaction; Risk Factors; RNA, Small Interfering
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1100626

Genome-wide association studies have revealed a large number of genetic associations with autoimmune diseases. Despite this progress, the mechanisms underlying the contribution of allelic variants to the onset of immune-related diseases remain mostly unknown. Our recent meta-analysis of genome-wide association studies of multiple sclerosis (MS) identified a new susceptibility locus tagged by a single nucleotide polymorphism, rs17824933 (p = 3.8 × 10(-9)), that is found in a block of linkage disequilibrium containing the CD6 gene. Because CD6 plays an important role in maintenance of T cell activation and proliferation, we examined the biologic phenotypes of the risk-associated allele. In this article, we report that the MS susceptibility allele in CD6 is associated with decreased expression of full-length CD6 in CD4(+) and CD8(+) T cells. As a consequence, proliferation is diminished during long-term activation of CD4(+) T cells from subjects with the risk allele. Selective knockdown of full-length CD6 using exon 5-specific small interfering RNA induces a similar proliferation defect of CD4(+) T cells from subjects homozygous for the protective allele. Exon 5 encodes for the extracellular binding site of the CD6 ligand ALCAM, which is required for CD6 stimulation. In CD4(+) T cells from subjects with the risk allele, exon 5 is consistently underexpressed, thereby providing a mechanism by which the allele affects proliferation of CD4(+) T cells. These findings indicate that the MS risk allele in the CD6 locus is associated with altered proliferation of CD4(+) T cells and demonstrate the influence of a disease-related allelic variant on important immunological characteristics.