Tu191 - A Risk Variant for Multiple Sclerosis Alters Tr1 Response to Vitamin D

Abstract Text: Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system resulting from an intricate interplay between genetic predisposition and environmental factors, such as Vitamin D (VD) deficiency. CD46 costimulation of human CD4+ T cells induces a switch from Th1 to type I regulatory cells (Tr1), characterized by increased IL-10 production. This switch is impaired in MS T cells but can be restored by VD, which also strongly promotes expression of CD226 on CD46-activated T cells. The rs763361 polymorphism in the CD226 gene, resulting in a non-synonymous Gly307Ser variant, is associated with increased risk for MS. Herein, we show that this CD226 risk allele disrupts the ability of CD46-activated T cells to operate the IFN/IL-10 switch upon VD exposure. Mechanistically, the risk variant impairs activation of the integrin LFA-1, which sustains homotypic adhesion associated with IL-10 production. LFA-1 activation is also impaired in MS T cells expressing the CD226 risk allele upon CD46 and VD stimulation. Furthermore, while MRI activities were independent of the genotype in the placebo group in the SOLARIUM trial, the only 2 pwMS with MRI activities after VD supplementation were homozygous for the CD226 risk allele. Although too small to be conclusive, this supports the hypothesis that the CD226 allele may impact response to VD in patients. Overall, our study unveils how, in the context of MS susceptibility, a genetic polymorphism and an environmental factor act in concert to control the differentiation of Tr1 cells.