MS genetic risk promotes IFNγ CD4 T cells.

Objective: To study the influence of the Abelson helper integration site 1 () locus associated with MS susceptibility on CD4 T cell function.

Methods: We characterized the chromatin state of T cells in the MS-associated linkage disequilibrium (LD) block. The expression and the role of the variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of was explored using T cells from knockout mice.

Results: Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, = 1.65 × 10), overlaps with strong enhancer regions that are present in human naive and memory CD4 T cells. Relative to the rs4896153 protective allele, the rs4896153 susceptibility allele is associated with decreased mRNA expression, specifically in naive CD4 T cells ( = 1.73 × 10, n = 213), and we replicate this effect in an independent set of subjects ( = 2.5 × 10, n = 32). Functional studies then showed that the rs4896153 risk variant and the subsequent decreased expression were associated with reduced CD4 T cell proliferation and a specific differentiation into interferon gamma (IFNγ)-positive T cells when compared with the protective rs4896153 allele. This T cell phenotype was also observed in murine CD4 T cells with genetic deletion of .

Conclusions: Our findings suggest that the effect of the genetic risk for MS is mediated, in part, by enhancing the development of proinflammatory IFNγ T cells that have previously been implicated in MS and its mouse models.