title: A 20-Mb region of chromosome 4 controls TNF-alpha-mediated CD8+ T cell aggression toward beta cells in type 1 diabetes.
abstract: 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.
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Giselle
authors.initials: G
authors.lastname: Chamberlain
authors.forename: Maja
authors.initials: M
authors.lastname: Wållberg
authors.forename: Dan
authors.initials: D
authors.lastname: Rainbow
authors.forename: Kara
authors.initials: K
authors.lastname: Hunter
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: E Allison
authors.initials: EA
authors.lastname: Green
mesh_terms: D000483:Alleles; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002875:Chromosomes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000473:pathology*; D007108:Immune Tolerance / Q000235:genetics; D007113:Immunity, Innate / Q000235:genetics; D050417:Insulin-Secreting Cells / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000276:immunology
chemical_list: D014409:Tumor Necrosis Factor-alpha