MS AHI1 genetic risk promotes IFNγ+ CD4+ T cells

Objective To study the influence of the Abelson helper integration site 1 ( AHI1 ) locus associated with MS susceptibility on CD4 + T cell function. Methods We characterized the chromatin state of T cells in the MS-associated AHI1 linkage disequilibrium (LD) block. The expression and the role of the AHI1 variant were examined in T cells from genotyped healthy subjects who were recruited from the PhenoGenetic Project, and the function of AHI1 was explored using T cells from Ahi1 knockout mice. Results Chromatin state analysis reveals that the LD block containing rs4896153, which is robustly associated with MS susceptibility (odds ratio 1.15, p = 1.65 × 10 −13 ), overlaps with strong enhancer regions that are present in human naive and memory CD4 + T cells. Relative to the rs4896153 A protective allele, the rs4896153 T susceptibility allele is associated with decreased AHI1 mRNA expression, specifically in naive CD4 + T cells ( p = 1.73 × 10 −74 , n = 213), and we replicate this effect in an independent set of subjects ( p = 2.5 × 10 −9 , n = 32). Functional studies then showed that the rs4896153 T risk variant and the subsequent decreased AHI1 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 A allele. This T cell phenotype was also observed in murine CD4 + T cells with genetic deletion of Ahi1 . Conclusions Our findings suggest that the effect of the AHI1 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.