title: The mouse idd2 locus is linked to the proportion of immunoregulatory double-negative T cells, a trait associated with autoimmune diabetes resistance.
abstract: Autoimmune diseases result from a break in immune tolerance. Various mechanisms of peripheral tolerance can protect against autoimmunity, including immunoregulatory CD4(-)CD8(-) double-negative (DN) T cells. Indeed, we have previously shown that diabetes-prone mouse strains exhibit a low proportion of DN T cells relative to that of diabetes-resistant mice, and that a single autologous transfer of DN T cells can impede autoimmune diabetes development, at least in the 3A9 TCR transgenic setting. In this study, we aim to understand the genetic basis for the difference in DN T cell proportion between diabetes-resistant and diabetes-prone mice. We thus perform an unbiased linkage analysis in 3A9 TCR F2 (NOD.H2(k) × B10.BR) mice and reveal that a locus on chromosome 9, which coincides with Idd2, is linked to the proportion of DN T cells in the lymph nodes. We generate two NOD.H2(k).B10-Chr9 congenic mouse strains and validate the role of this genetic interval in defining the proportion of DN T cells. Moreover, we find that the increased proportion of DN T cells in lymphoid organs is associated with a decrease in both diabetes incidence and serum IgG Ab levels. Together, the data suggest that Idd2 is linked to DN T cell proportion and that a physiological increase in DN T cell number may be sufficient to confer resistance to autoimmune diabetes. Altogether, these findings could help identify new candidate genes for the development of therapeutic avenues aimed at modulating DN T cell number for the prevention of autoimmune diseases.
authors.affiliation: Division of Immunology-Oncology, Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; and.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Collin
authors.affiliation: Division of Immunology-Oncology, Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; and.
authors.forename: Véronique
authors.initials: V
authors.lastname: Dugas
authors.affiliation: Division of Immunology-Oncology, Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; and.
authors.forename: Adam-Nicolas
authors.initials: AN
authors.lastname: Pelletier
authors.affiliation: Division of Immunology-Oncology, Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada;
authors.forename: Geneviève
authors.initials: G
authors.lastname: Chabot-Roy
authors.affiliation: Division of Immunology-Oncology, Research Center, Maisonneuve-Rosemont Hospital, Montreal, Quebec H1T 2M4, Canada; Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montreal, Quebec H3C 3J7, Canada; and Department of Microbiology and Immunology, McGill University, Montreal, Quebec H3A 0G4, Canada sylvie.lesage@gmail.com.
authors.forename: Sylvie
authors.initials: S
authors.lastname: Lesage
mesh_terms: D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D007074:Immunoglobulin G / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D040641:Quantitative Trait Loci / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D013601:T-Lymphocytes
chemical_list: D007074:Immunoglobulin G; D011948:Receptors, Antigen, T-Cell