title: Expression of diabetes-associated genes by dendritic cells and CD4 T cells drives the loss of tolerance in nonobese diabetic mice.
abstract: 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.
authors: Department of Immunology and Microbial Sciences, The Scripps Research Institute, La Jolla, CA 92037, USA.
authors: Emma E
authors: EE
authors: Hamilton-Williams
authors: Xavier
authors: X
authors: Martinez
authors: Jan
authors: J
authors: Clark
authors: Sarah
authors: S
authors: Howlett
authors: Kara M
authors: KM
authors: Hunter
authors: Daniel B
authors: DB
authors: Rainbow
authors: Li
authors: L
authors: Wen
authors: Mark J
authors: MJ
authors: Shlomchik
authors: Jonathan D
authors: JD
authors: Katz
authors: Georg F
authors: GF
authors: Beilhack
authors: Linda S
authors: LS
authors: Wicker
authors: Linda A
authors: LA
authors: Sherman
mesh_terms: D000483:Alleles; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes; D017637:Clonal Deletion; D003713:Dendritic Cells / Q000378:metabolism* / Q000473:pathology; D003920:Diabetes Mellitus / Q000235:genetics*; D015870:Gene Expression; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D017634:Self Tolerance / Q000276:immunology*
chemical_list: D001324:Autoantigens