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* Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037;
Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom;
Section of Endocrinology, Yale School of Medicine, New Haven, Connecticut;
Diabetes Research Center, Division of Endocrinology and Division of Molecular Immunology, Department of Pediatrics, Cincinnati Children’s Research Foundation and the University of Cincinnati College of Medicine, Cincinnati OH 45229; and
¶ Department of Internal Medicine III, University of Vienna, Austria
In humans and NOD mice, defects in immune tolerance result in the spontaneous development of type-1-diabetes. Recent studies have ascribed a breakdown in tolerance to dysfunction in regulatory T cells that is secondary to reduced IL-2 production by T cells having the NOD diabetes susceptibility region insulin-dependent diabetes 3 (Idd3). In this study, we demonstrate a peripheral tolerance defect in the dendritic cells of NOD mice that is independent of regulatory T cells. NOD CD8 T cells specific for islet Ags fail to undergo deletion in the pancreatic lymph nodes. Deletion was promoted by expression of the protective alleles of both Idd3 (Il2) and Idd5 in dendritic cells. We further identify a second tolerance defect that involves endogenous CD4 T cell expression of the disease-promoting NOD alleles of these genetic regions. Pervasive insulitis can be reduced by expression of the Idd3 and Idd5 protective alleles by either the Ag-presenting cell or lymphocytes.
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1 This work was supported by National Institute of Allergy and Infectious Disease (NIAID) Grant AI 070351. E.H.W. and X.M. supported by postdoctoral fellowships from the Juvenile Diabetes Research Foundation (JDRF). L.S.W. is supported by grants from the JDRF and the Wellcome Trust and L.S.W. is a Wellcome Trust Principal Research Fellow. The Cambridge Institute for Medical Research is the recipient of a Wellcome Trust Strategic Award (079895). The availability of NOD congenic mice through the Taconic Farms Emerging Models Program has been supported by grants from the Merck Genome Research Institute, NIAID, and the JDRF.
2 E.E.H.-W. and X.M. contributed equally to this work.
3 L.S.W. and L.A.S. are senior authors and contributed equally to this work.
4 Address correspondence and reprint requests to Dr. Linda A. Sherman, Department of Immunology and Microbial Sciences, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037. E-mail address: lsherman{at}scripps.edu
5 Abbreviations used in this paper: T1D, type-1-diabetes; Idd, insulin-dependent diabetes; PcLN, pancreatic lymph node; Treg, regulatory T cell; DC, dendritic cell; BM, bone marrow; β2M, β2-microglobulin; HA, hemagglutinin; DT, diphtheria toxin; DTR, DT receptor; ACADL, acyl-coenzyme A dehydrogenase long chain.
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