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 3

The CD8+ T cells from most T1D patients tested could be boosted in vitro to restore their function.

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The CD8+ T cells from most T1D patients tested could be boosted in vitro...
(A) CD8+ T cells from a T1D patient restored the capacity to specifically recognize the target structure HLA-E/Hsp60sp, after being boosted in vitro with autologous DCs loaded with Hsp60sp peptide. CD8(H) and control CD8+ lines were generated from each T1D patient and corresponding normal control and were tested and compared in a CD8+ T cell inhibition assay. Data are shown as mean ± SEM and are representative of 8 of 9 T1D patients who originally tested with a defect of the HLA-E–restricted CD8+ T cells. (B) CD8+ T cells from a T1D patient restored the capacity to discriminate self from nonself after an in vitro boost with autologous DCs loaded with Hsp60sp peptide. CD8(H) and control CD8(B) lines were generated from each T1D patient and corresponding normal control and tested and compared in a self/nonself discrimination assay. Data are shown as mean ± SEM and are representative of 8 of 9 T1D patients who originally tested with defect of the HLA-E–restricted CD8+ T cells. (C) CD8+ T cells from most T1D patients tested regain the capacity to discriminate self from nonself after an in vitro boost. Immune responses of in vitro established CD8(H) lines to self-antigen GAD versus to foreign antigen TT were compared with those of CD8(B) and CD8(N) lines in each T1D patient, paired with normal control. Data summarize 10 T1D patients and correspondent controls and are representative of 2 tests for each patient.