Activation-induced cytidine deaminase expression by thymic B cells promotes T-cell tolerance and limits autoimmunity
Félix Lombard-Vadnais,
Geneviève Chabot-Roy,
Astrid Zahn,
Sahily Rodriguez Torres,
Javier M. Di Noia,
Heather J. Melichar,
Sylvie Lesage
Affiliations
Félix Lombard-Vadnais
Immunologie-oncologie, Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; Department of Microbiology & Immunology, McGill University, Montreal, QC H3A 0G4, Canada
Geneviève Chabot-Roy
Immunologie-oncologie, Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada
Astrid Zahn
Unité de recherche en biologie moléculaire des cellules B, Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada
Sahily Rodriguez Torres
Immunologie-oncologie, Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC H3T 1J4, Canada
Javier M. Di Noia
Department of Microbiology & Immunology, McGill University, Montreal, QC H3A 0G4, Canada; Unité de recherche en biologie moléculaire des cellules B, Institut de recherches cliniques de Montréal, Montréal, QC H2W 1R7, Canada; Département de médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Department of Experimental Medicine, McGill University, Montreal, QC H3A 0G4, Canada
Heather J. Melichar
Immunologie-oncologie, Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; Département de médecine, Université de Montréal, Montréal, QC H3T 1J4, Canada; Corresponding author
Sylvie Lesage
Immunologie-oncologie, Centre de recherche de l’Hôpital Maisonneuve-Rosemont, Montréal, QC H1T 2M4, Canada; Département de microbiologie, infectiologie et immunologie, Université de Montréal, Montréal, QC H3T 1J4, Canada; Corresponding author
Summary: Elimination of self-reactive T cells in the thymus is critical to establish T-cell tolerance. A growing body of evidence suggests a role for thymic B cells in the elimination of self-reactive thymocytes. To specifically address the role of thymic B cells in central tolerance, we investigated the phenotype of thymic B cells in various mouse strains, including non-obese diabetic (NOD) mice, a model of autoimmune diabetes. We noted that isotype switching of NOD thymic B cells is reduced as compared to other, autoimmune-resistant, mouse strains. To determine the impact of B cell isotype switching on thymocyte selection and tolerance, we generated NOD.AID−/− mice. Diabetes incidence was enhanced in these mice. Moreover, we observed reduced clonal deletion and a resulting increase in self-reactive CD4+ T cells in NOD.AID−/− mice relative to NOD controls. Together, this study reveals that AID expression in thymic B cells contributes to T-cell tolerance.
