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-Ag7-restricted T-cell receptor (TCR) (4.1-TCR) undergo negative selection in mice carrying one copy of the antidiabetogenic H-2b haplotype in an I-Ab-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-Ad, I-Ag7PD, or I-Eαk 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 β1 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.
Address correspondence and reprint requests to Dr. Pere Santamaria, Department of Microbiology and Infectious Diseases, Faculty of Medicine, University of Calgary, Health Sciences Centre, 3330 Hospital Dr. N.W., Calgary, Alberta T2N 4N1, Canada. E-mail:.
Received for publication 17 May 2001 and accepted in revised form 24 October 2001.
APC, antigen-presenting cell; BrdU, 5-bromo-2′-deoxyuridine; CLIP, class II-associated invariant chain peptide; FITC, fluorescein isothiocyanate; H/E, hematoxylin and eosin; IFN-γ, γ-interferon; IL, interleukin; mAb, monoclonal antibody; MHC, major histocompatibility complex; PMA, phorbol-myristate acetate; RAG-2, recombination activating gene-2; TCR, T-cell receptor.