title: T-cell tolerance by dendritic cells and macrophages as a mechanism for the major histocompatibility complex-linked resistance to autoimmune diabetes.
abstract: For poorly understood reasons, the development of autoimmune diabetes in humans and mice is dominantly inhibited by major histocompatibility complex (MHC) class II molecules with diverse antigen-binding sites. We have previously shown that thymocytes expressing a highly diabetogenic I-A(g7)-restricted T-cell receptor (TCR) (4.1-TCR) undergo negative selection in mice carrying one copy of the antidiabetogenic H-2(b) haplotype in an I-A(b)-dependent but superantigen-independent manner. Here, we show that 4.1-TCR-transgenic thymocytes undergo different forms of tolerance in NOD mice expressing antidiabetogenic I-A(d), I-A(g7PD), or I-Ealpha(k) transgenes. The ability of protective MHC class II molecules to induce thymocyte tolerance in 4.1-TCR-transgenic NOD mice correlates with their ability to prevent diabetes in non-TCR-transgenic mice and is associated with polymorphisms within positions 56-67 of their beta1 domains. The 4.1-thymocyte tolerogenic activity of these MHC class II molecules is mediated by dendritic cells and macrophages but not by B-cells or thymic epithelial cells and is a peptide-dependent process. Antidiabetogenic MHC class II molecules may thus afford diabetes resistance by presenting, on dendritic cells and macrophages, tolerogenic peptides to a subset of highly diabetogenic and MHC-promiscuous CD4(+) T-cells that play a critical role in the initiation of diabetes.
authors.affiliation: Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Shari
authors.initials: S
authors.lastname: Thiessen
authors.forename: Pau
authors.initials: P
authors.lastname: Serra
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Amrani
authors.forename: Joan
authors.initials: J
authors.lastname: Verdaguer
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D002455:Cell Division / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004198:Disease Susceptibility / Q000276:immunology; D006412:Hematopoietic Stem Cells / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D007515:Islets of Langerhans / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D013269:Stochastic Processes; D013601:T-Lymphocytes / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000502:physiology
chemical_list: D000949:Histocompatibility Antigens Class II; D011948:Receptors, Antigen, T-Cell