The level of peptide-MHC complex determines the susceptibility to autoimmune diabetes: Studies in HEL transgenic mice

Richard J. DiPaolo, Emil R. Unanue

Research output: Contribution to journalArticlepeer-review

17 Scopus citations

Abstract

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-Ak 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 peripancreatic 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 auto-immunity.

Original languageEnglish
Pages (from-to)3453-3459
Number of pages7
JournalEuropean Journal of Immunology
Volume31
Issue number12
DOIs
StatePublished - 2001

Keywords

  • Antigen presentation
  • Autoimmunity
  • Cross-presentation
  • Diabetes
  • Tolerance

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