HLA-E–restricted regulatory CD8+ T cells are involved in development and control of human autoimmune type 1 diabetes
Hong Jiang, … , Zongyu Zheng, Leonard Chess
Hong Jiang, … , Zongyu Zheng, Leonard Chess
Published September 27, 2010
Citation Information: J Clin Invest. 2010;120(10):3641-3650. https://doi.org/10.1172/JCI43522.
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Research Article

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

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.

Authors

Hong Jiang, Steve M. Canfield, Mary P. Gallagher, Hong H. Jiang, Yihua Jiang, Zongyu Zheng, Leonard Chess

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Figure 1

Generation of human HLA-E–restricted CD8+ T cell lines that function to discriminate self from nonself by specifically recognizing HLA-E/Hsp60sp expressed on the target cells.

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Generation of human HLA-E–restricted CD8+ T cell lines that function to ...
(A) CD8(H) lines from healthy individuals specifically inhibit HLA-E–expressing cells loaded with Hsp60sp. CD8(H) and control lines were generated and tested in a CD8+ T cell inhibition assay as described in Methods. Data represent mean ± SEM and were from 3 healthy normal individuals. Ctr pep, control peptide. (B) Increased CE expression by the HLA-E–restricted CD8+ T cells triggered by the specific target structure HLA-E/Hsp60sp. CD8(H) and CD(B) lines from healthy individuals were cocultured with B721/E cells loaded with peptide Hsp60sp or control peptide B7sp. The CE expression by the CD8+ T cells was detected by 3-color intracellular staining with perforin (Perf), granzyme A (GA), and granzyme B (GB), followed by FACS analysis as described in Methods. Shown are representative data from 1 of 3 healthy normal individuals. Top row: CE expression indexes of 3 different combinations of CE expression; bottom row: intracellular staining patterns of the CEs on the CD8(H) lines. (C) CD8(H) lines from healthy individuals suppress the overall immune responses to self-antigens MBP and GAD but enhance the immune responses to foreign antigens TT and PPD. CD8(H) and control CD8(B) lines were generated and tested in a self/nonself discrimination assay as described in Methods. Data are shown as mean ± SEM and were from 3 healthy normal individuals. 3Hdtr, [3H]thymidine. YRK, YL, and AJ designate individual normal healthy controls.