Key Points
NOD.Idd2 mice are strongly protected from autoimmune diabetes.
Idd2-mediated diabetes protection is immune cell intrinsic.
Idd2 locus genetic variants impact germinal center formation and MHC expression.
Abstract
Type 1 diabetes is an autoimmune disease characterized by pancreatic β cell destruction. It is a complex genetic trait driven by >30 genetic loci with parallels between humans and mice. The NOD mouse spontaneously develops autoimmune diabetes and is widely used to identify insulin-dependent diabetes (Idd) genetic loci linked to diabetes susceptibility. Although many Idd loci have been extensively studied, the impact of the Idd2 locus on autoimmune diabetes susceptibility remains to be defined. To address this, we generated a NOD congenic mouse bearing B10 resistance alleles on chromosome 9 in a locus coinciding with part of the Idd2 locus and found that NOD.B10-Idd2 congenic mice are highly resistant to diabetes. Bone marrow chimera and adoptive transfer experiments showed that the B10 protective alleles provide resistance in an immune cell–intrinsic manner. Although no T cell–intrinsic differences between NOD and NOD.B10-Idd2 mice were observed, we found that the Idd2 resistance alleles limit the formation of spontaneous and induced germinal centers. Comparison of B cell and dendritic cell transcriptome profiles from NOD and NOD.B10-Idd2 mice reveal that resistance alleles at the Idd2 locus affect the expression of specific MHC molecules, a result confirmed by flow cytometry. Altogether, these data demonstrate that resistance alleles at the Idd2 locus impair germinal center formation and influence MHC expression, both of which likely contribute to reduced diabetes incidence.
Footnotes
This work was supported by the Natural Sciences and Engineering Research Council of Canada (2019-05047), the Canadian Diabetes Association (OG-3-13-4018), and a Diabète Québec grant, all awarded to S.L., as well as by a grant from the Canadian Institutes of Health Research (PJT-168910) awarded to N.L. F.L.-V. holds scholarships from the Cole Foundation and la Fondation de l'Hôpital Maisonneuve-Rosemont. F.L.-V. and R.C. are recipients of PhD scholarships from and S.L. is a Research Scholar Emeritus supported by Fonds de Recherche du Québec – Santé.
The online version of this article contains supplemental material.
- Received May 14, 2021.
- Accepted December 2, 2021.
- Copyright © 2022 by The American Association of Immunologists, Inc.
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