Multiple sclerosis-associated CD226 variant disrupts vitamin D-induced type I Treg differentiation by impairing LFA-1 activation
Abstract
Multiple sclerosis (MS) is a complex inflammatory disease of the CNS resulting from an intricate interplay between genetic predisposition and environmental factors. Vitamin D (VD) deficiency is one of the established risk factors for MS. CD46 costimulation of 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 nonsynonymous Gly307Ser variant, is associated with increased risk for MS. Herein, we show that expression of this CD226 risk allele disrupts the ability of CD46-activated T cells to operate the IFN-γ/IL-10 switch upon VD exposure. Mechanistically, the risk variant impairs activation of the integrin LFA-1, which promotes the Tr1 phenotype. LFA-1-mediated Tr1 differentiation is also impaired in MS T cells expressing the CD226 risk allele upon CD46 and VD stimulation. 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.
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BibTeX
@article{kari2026multiple,
title = {{Multiple sclerosis-associated CD226 variant disrupts vitamin D-induced type I Treg differentiation by impairing LFA-1 activation}},
author = {Saniya Kari and Aymeline Debonlier and Thibault Angles and Beatriz Chaves and Charles Grosjean and Florence Bucciarelli and Valérie Duplan-Eche and Lucie Nozeran and Jessica Lavery and Elena Morandi and Beatrice Pignolet and Max Mimpen and Joost Smolders and Roland Liblau and Abdelhadi Saoudi and Jan Damoiseaux and Frederick Masson and Loïc Dupré and Anne Laurence Astier},
journal = {The Journal of clinical investigation},
year = {2026},
month = sep,
doi = {10.1172/jci202193},
url = {https://hal.science/hal-05752803v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Multiple sclerosis-associated CD226 variant disrupts vitamin D-induced type I Treg differentiation by impairing LFA-1 activation
AU - Saniya Kari
AU - Aymeline Debonlier
AU - Thibault Angles
AU - Beatriz Chaves
AU - Charles Grosjean
AU - Florence Bucciarelli
AU - Valérie Duplan-Eche
AU - Lucie Nozeran
AU - Jessica Lavery
AU - Elena Morandi
AU - Beatrice Pignolet
AU - Max Mimpen
AU - Joost Smolders
AU - Roland Liblau
AU - Abdelhadi Saoudi
AU - Jan Damoiseaux
AU - Frederick Masson
AU - Loïc Dupré
AU - Anne Laurence Astier
PY - 2026
DA - 2026/09/01
JO - The Journal of clinical investigation
DO - 10.1172/jci202193
UR - https://hal.science/hal-05752803v1
AB - Multiple sclerosis (MS) is a complex inflammatory disease of the CNS resulting from an intricate interplay between genetic predisposition and environmental factors. Vitamin D (VD) deficiency is one of the established risk factors for MS. CD46 costimulation of 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 nonsynonymous Gly307Ser variant, is associated with increased risk for MS. Herein, we show that expression of this CD226 risk allele disrupts the ability of CD46-activated T cells to operate the IFN-γ/IL-10 switch upon VD exposure. Mechanistically, the risk variant impairs activation of the integrin LFA-1, which promotes the Tr1 phenotype. LFA-1-mediated Tr1 differentiation is also impaired in MS T cells expressing the CD226 risk allele upon CD46 and VD stimulation. 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.
SN - 1558-8238
ER -