The level of peptide-MHC complex determines the susceptibility to autoimmune diabetes: studies in HEL transgenic mice.
We report a mouse model for the spontaneous development of autoimmune diabetes: the 3A9 T cell receptor (TCR) transgenic mouse, which contains T cells that recognize the 52 - 61 family of hen egg-white lysozyme (HEL) peptides in the context of MHC class II I-A(k) molecules, was bred to the ILK3 mouse, that expresses HEL protein via the rat insulin promoter (RIP). Despite partial tolerance of 3A9 T cells in ILK3 mice, spontaneous diabetes developed in 64 % of 3A9xILK3 mice by 20 weeks of age. We provide evidence that APC from peri-pancreatic nodes have a large content of peptide-MHC complex and stimulate 3A9 T cells. We also report that cross presentation of HEL from beta cells to APC is 26-fold more efficient than presentation of soluble HEL. We previously reported on a biochemical margin of safety, based on the observation that activation of naive 3A9 T cells required 100-fold more peptide-MHC complexes than required for deletion of 3A9 thymocytes. We speculate that the high local density of autologous peptide-MHC complexes can be a determining factor that leads to the activation of autoreactive CD4 T cells and, consequently, to the development of autoimmunity.
DiPaolo
R J
RJ
Department of Pathology and Immunology and Center for Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Unanue
E R
ER
D000818:Animals; D017951:Antigen Presentation; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology*; D004198:Disease Susceptibility; D006649:Histocompatibility Antigens / Q000378:metabolism*; D007515:Islets of Langerhans / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology*; D013601:T-Lymphocytes / Q000502:physiology
D006649:Histocompatibility Antigens; C421864:hen egg lysozyme; D009113:Muramidase