HLA-E–restricted regulatory CD8+ T cells are involved in development and control of human autoimmune type 1 diabetes
Hong Jiang, Steve M. Canfield, Mary P. Gallagher, Hong H. Jiang, Yihua Jiang, Zongyu Zheng, Leonard Chess
Hong Jiang, Steve M. Canfield, Mary P. Gallagher, Hong H. Jiang, Yihua Jiang, Zongyu Zheng, Leonard Chess
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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.