Multiple sclerosis-associated CD226 variant disrupts vitamin D-induced type I Treg differentiation by impairing LFA-1 activation

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 non-synonymous 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 IFNγ/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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Publication Details

Journal
Journal of Clinical Investigation
Published
2026-09-01
DOI
https://doi.org/10.1172/jci202193
Primary Topic
Immune Cell Function and Interaction
Type
article
Field-Weighted Citation Impact
0.00

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article

Multiple sclerosis-associated CD226 variant disrupts vitamin D-induced type I Treg differentiation by impairing LFA-1 activation

Frédérick Masson, Florence Bucciarelli, Elena Morandi, Thibault Angles et al.
Journal of Clinical Investigation
Immune Cell Function and Interaction
article

Multiple sclerosis-associated CD226 variant disrupts vitamin D-induced type I Treg differentiation by impairing LFA-1 activation

Frédérick Masson, Florence Bucciarelli, Elena Morandi, Thibault Angles, Loı̈c Dupré, Max Mimpen, Anne Astier, Béatrice Pignolet, Charles Grosjean, Abdelhadi Saoudi, Saniya Kari, Valérie Duplan-Eche, J. J. Lavery, Roland Liblau, Aymeline Debonlier, B. P. Chaves, Jan Damoiseaux, Joost Smolders, Lucie Nozeran
article en

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 non-synonymous 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 IFNγ/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.

Journal of Clinical Investigation
Centre National de la Recherche Scientifique (FR), Inserm (FR), Université Fédérale de Toulouse Midi-Pyrénées (FR), Erasmus MC (NL), Maastricht University (NL), Toulouse Mathematics Institute (FR), Institut des Maladies Métaboliques et Cardiovasculaires (FR), Institut Toulousain des Maladies Infectieuses et Inflammatoires (FR)
Agence Nationale de la Recherche, Institut National de la Santé et de la Recherche Médicale, Radboud Universiteit, University of Toronto, Centre National de la Recherche Scientifique, Radboud Universitair Medisch Centrum
Openalex Percentile: Top 17%
Immune Cell Function and Interaction
DOIOpen Access PDFOpenAlex
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