MHC Class II Molecules Play a Role in the Selection of Autoreactive Class I-Restricted CD8 T Cells that are Essential Contributors to Type 1 Diabetes Development in Nonobese Diabetic Mice

David V. Serreze, T. Matthew Holl, Michele P. Marron, Robert T. Graser, Ellis A. Johnson, Caroline Choisy-Rossi, Robyn M. Slattery, Scott M. Lieberman, Teresa P. DiLorenzo

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Development of autoreactive CD4 T cells contributing to type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is either promoted or dominantly inhibited by particular MHC class II variants. In addition, it is now clear that when co-expressed with other susceptibility genes, some common MHC class I variants aberrantly mediate autoreactive CD8 T cell responses also essential to T1D development. However, it was unknown whether the development of diabetogenic CD8 T cells could also be dominantly inhibited by particular MHC variants. We addressed this issue by crossing NOD mice transgenically expressing the TCR from the diabetogenic CD8 T cell clone AI4 with NOD stocks congenic for MHC haplotypes that dominantly inhibit T1D. High numbers of functional AI4 T cells only developed in controls homozygously expressing NOD-derived H2g7 molecules. In contrast, heterozygous expression of some MHC haplotypes conferring T1D resistance anergized AI4 T cells through decreased TCR (H2b) or CD8 expression (H2q). Most interestingly, while AI4 T cells exert a class I-restricted effector function, H2nb1 MHC class II molecules can contribute to their negative selection. These findings provide insights to how particular MHC class I and class II variants interactively regulate the development of diabetogenic T cells and the TCR promiscuity of such autoreactive effectors.

Original languageEnglish (US)
Pages (from-to)871-879
Number of pages9
JournalJournal of Immunology
Volume172
Issue number2
DOIs
StatePublished - Jan 15 2004

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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