title: TCR transgenic mice reveal the impact of type 1 diabetes loci on early and late disease checkpoints.
abstract: Linkage analysis studies for autoimmune diabetes have revealed multiple non-major histocompatibility complex (MHC) chromosomal regions linked to disease susceptibility. To date, more than 20 insulin-dependent diabetes (Idd) loci linked to diabetes susceptibility have been identified in NOD mice and validated via congenic breeding. Importantly, evidence suggests that Idd loci may regulate at least two pathological steps during autoimmune diabetes development, namely the onset of insulitis and the transition from insulitis to overt diabetes. Here we assess the role of various non-MHC Idd diabetes-resistance loci, which have been validated in the non-transgenic setting, on autoimmune diabetes progression in the transgenic setting. Specifically, we generated multiple Idd congenic strains in the 3A9-TCR:insHEL NOD.H2(k) transgenic model and monitored their diabetes incidence. We show that 3A9-TCR:insHEL NOD.H2(k) mice congenic for Idd3 or Idd5 display a reduction in diabetes development, whereas mice congenic for Idd9 or Idd13 exhibit an increase, in comparison with 3A9-TCR:insHEL NOD.H2(k) mice. These results suggest that the presence of the 3A9-TCR and hen egg lysosyme transgenes can offset the regulatory function of certain diabetes-resistance genetic variants contained within the Idd loci, including Idd9 and Idd13. We propose the antigen-specific 3A9-TCR:insHEL transgenic model as a useful tool for the study of the genetics of autoimmune diabetes development.
authors.affiliation: Immunology-Oncology Section, Research Center, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Erin E
authors.initials: EE
authors.lastname: Hillhouse
authors.affiliation: Autoimmune Genetics Laboratory, Department of Microbiology and Immunology, VIB, Leuven, Belgium.|University of Leuven, Leuven, Belgium.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
authors.affiliation: Immunology-Oncology Section, Research Center, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Roxanne
authors.initials: R
authors.lastname: Collin
authors.affiliation: Immunology-Oncology Section, Research Center, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Eric
authors.initials: E
authors.lastname: Desautels
authors.affiliation: Department of Immunology, John Curtin School of Medical Research, Australian National University, Canberra, Australian Capital Territory, Australia.|Immunogenomics Group, Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Christopher C
authors.identifier: 0000-0001-5296-6155
authors.initials: CC
authors.lastname: Goodnow
authors.affiliation: Immunology-Oncology Section, Research Center, Maisonneuve-Rosemont Hospital, Montréal, Québec, Canada.|Département de Microbiologie, Infectiologie et Immunologie, Université de Montréal, Montréal, Québec, Canada.
authors.forename: Sylvie
authors.identifier: 0000-0002-0968-2795
authors.initials: S
authors.lastname: Lesage
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics* / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics* / Q000276:immunology*; D060467:Disease Resistance / Q000235:genetics; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*
chemical_list: D011948:Receptors, Antigen, T-Cell