title: Dendritic cell-dependent in vivo generation of autoregulatory T cells by antidiabetogenic MHC class II.
abstract: Several mechanisms have been proposed to explain how certain MHC class II molecules afford dominant resistance to autoimmune diseases like type 1 diabetes (T1D). However, it remains unclear how protective MHC types can blunt autoreactive T cell responses directed against a diverse repertoire of autoantigenic epitopes presented by disease-promoting MHCs. In this study, we show that expression of I-E on dendritic cells (DCs) of NOD mice promotes the differentiation of MHC promiscuous autoreactive CD4(+) clonotypes into antidiabetogenic autoregulatory T cells. We expressed an I-Eα(kloxP) transgene in NOD mice and used cell type-specific I-E ablation to show that I-E-expressing DCs, but not B cells, promote the generation of autoreactive CD4(+)Foxp3(+) regulatory T cells (Tregs) and their accumulation in the pancreas-draining lymph nodes. There, these Tregs suppress the presentation of β cell Ags to naive autoreactive CD4(+) and CD8(+) T cells restricted by diabetogenic MHC molecules in an I-E-independent manner. Whereas selective removal of I-E on DCs abrogated autoregulatory Treg formation and T1D protection, selective removal of I-E on B cells was inconsequential. These results explain how certain MHC class II molecules can completely suppress antigenically complex autoimmune responses in an Ag-nonspecific manner.
authors.affiliation: Department of Microbiology, Immunology and Infectious Diseases and Julia McFarlane Diabetes Research Centre, Snyder Institute for Chronic Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Sue
authors.initials: S
authors.lastname: Tsai
authors.forename: Pau
authors.initials: P
authors.lastname: Serra
authors.forename: Xavier
authors.initials: X
authors.lastname: Clemente-Casares
authors.forename: Robyn M
authors.initials: RM
authors.lastname: Slattery
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D003921:Diabetes Mellitus, Experimental / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D005802:Genes, MHC Class II / Q000235:genetics / Q000276:immunology*; D019426:Integrases / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology
chemical_list: C045073:Cre recombinase; D019426:Integrases