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ResearchIn-Press PreviewAutoimmunityImmunologyInflammation Open Access | 10.1172/JCI202193

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

Saniya Kari,1 Aymeline Debonlier,1 Thibault Angles,1 Beatriz Chaves,1 Charles Grosjean,1 Florence Bucciarelli,1 Valérie Duplan-Eche,1 Lucie Nozeran,1 Jessica Lavery,1 Elena Morandi,1 Beatrice Pignolet,1 Max Mimpen,2 Joost Smolders,3 Roland Liblau,1 Abdelhadi Saoudi,1 Jan Damoiseaux,4 Frederick Masson,1 Loïc Dupré,1 and Anne L. Astier1

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Kari, S. in: PubMed | Google Scholar |

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Debonlier, A. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Angles, T. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Chaves, B. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Grosjean, C. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Bucciarelli, F. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Duplan-Eche, V. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Nozeran, L. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Lavery, J. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Morandi, E. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Pignolet, B. in: PubMed | Google Scholar |

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Mimpen, M. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Smolders, J. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Liblau, R. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Saoudi, A. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Damoiseaux, J. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Masson, F. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Dupré, L. in: PubMed | Google Scholar

1Univ Toulouse, Toulouse Institute for Infectious and Inflammatory Diseases (Infinity), INSERM UMR1291 – CNRS UMR5051, Toulouse, France

2School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands

3MS Center ErasMS, Departments of Neurology and Immunology, Erasmus University Medical Center, Rotterdam, Netherlands

4Central Diagnostic Laboratory, Maastricht University Medical Center, Maastricht, Netherlands

Find articles by Astier, A. in: PubMed | Google Scholar |

Published September 1, 2026 - More info

J Clin Invest. https://doi.org/10.1172/JCI202193.
Copyright © 2026, Kari et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published September 1, 2026 - Version history
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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.

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