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Identification of candidate genes and their immunological mechanisms that control autoaggressive T cells in inflamed environments, may lead to novel therapies for autoimmune diseases, like type 1 diabetes (T1D). In this study, we used transgenic NOD mice that constitutively express TNF-alpha in their islets from neonatal life (TNF-alpha-NOD) to identify protective alleles that control T1D in the presence of a proinflammatory environment. We show that TNF-alpha-mediated breakdown in T cell tolerance requires recessive NOD alleles. To identify some of these recessive alleles, we crossed TNF-alpha-NOD mice to diabetes-resistant congenic NOD mice having protective alleles at insulin-dependent diabetes (Idd) loci that control spontaneous T1D at either the preinsulitis (Idd3.Idd5) or postinsulitis (Idd9) phases. No protection from TNF-alpha-accelerated T1D was afforded by resistance alleles at Idd3.Idd5. Lack of protection was not at the level of T cell priming, the efficacy of islet-infiltrating APCs to present islet peptides, nor the ability of high levels of CD4+ Foxp3+ T cells to accumulate in the islets. In contrast, protective alleles at Idd9 significantly increased the age at which TNF-alpha-NOD mice developed T1D. Disease delay was associated with a decreased ability of CD8+ T cells to respond to islet Ags presented by islet-infiltrating APCs. Finally, we demonstrate that the protective region on chromosome 4 that controls T1D in TNF-alpha-Idd9 mice is restricted to the Idd9.1 region. These data provide new evidence of the mechanisms by which selective genetic loci control autoimmune diseases in the presence of a strong inflammatory assault.

Original publication

DOI

10.4049/jimmunol.177.8.5105

Type

Journal article

Journal

Journal of immunology (Baltimore, Md. : 1950)

Publication Date

10/2006

Volume

177

Pages

5105 - 5114

Addresses

Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.

Keywords

CD8-Positive T-Lymphocytes, T-Lymphocytes, Cytotoxic, Chromosomes, Animals, Mice, Inbred NOD, Mice, Transgenic, Mice, Diabetes Mellitus, Type 1, Tumor Necrosis Factor-alpha, Immune Tolerance, Antigen Presentation, Alleles, Insulin-Secreting Cells, Immunity, Innate