HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes

J Clin Invest. 2010 Oct;120(10):3641-50. doi: 10.1172/JCI43522. Epub 2010 Sep 27.

Abstract

A key feature of the immune system is its ability to discriminate self from nonself. Breakdown in any of the mechanisms that maintain unresponsiveness to self (a state known as self-tolerance) contributes to the development of autoimmune conditions. Recent studies in mice show that CD8(+) T cells specific for the unconventional MHC class I molecule Qa-1 bound to peptides derived from the signal sequence of Hsp60 (Hsp60sp) contribute to self/nonself discrimination. However, it is unclear whether they exist in humans and play a role in human autoimmune diseases. Here we have shown that CD8(+) T cells specific for Hsp60sp bound to HLA-E (the human homolog of Qa-1) exist and play an important role in maintaining peripheral self-tolerance by discriminating self from nonself in humans. Furthermore, in the majority of type 1 diabetes (T1D) patients tested, there was a specific defect in CD8(+) T cell recognition of HLA-E/Hsp60sp, which was associated with failure of self/nonself discrimination. However, the defect in the CD8(+) T cells from most of the T1D patients tested could be corrected in vitro by exposure to autologous immature DCs loaded with the Hsp60sp peptide. These data suggest that HLA-E-restricted CD8(+) T cells may play an important role in keeping self-reactive T cells in check. Thus, correction of this defect could be a potentially effective and safe approach in the therapy of T1D.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • CD8-Positive T-Lymphocytes / physiology*
  • Cell Line
  • Chaperonin 60 / immunology
  • Diabetes Mellitus, Type 1 / etiology*
  • Diabetes Mellitus, Type 1 / immunology
  • HLA Antigens / physiology*
  • Histocompatibility Antigens Class I / physiology*
  • Humans
  • Molecular Sequence Data
  • T-Lymphocytes, Regulatory / physiology*

Substances

  • Chaperonin 60
  • HLA Antigens
  • HLA-E antigen
  • Histocompatibility Antigens Class I