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 2

A defect in the HLA-E–restricted CD8+ T cell–mediated pathway is detected in a majority of the T1D patients tested.

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A defect in the HLA-E–restricted CD8+ T cell–mediated pathway is detecte...
(A) Freshly isolated CD8+ T cells from a T1D patient lost the capacity to specifically recognize HLA-E/Hsp60sp target structure. CD8+ T cells were purified from T1D patients and tested in a CD8+ T cell inhibition assay as described in Methods. Data show mean ± SEM and are representative of 9 of 10 T1D patients tested (P) paired with healthy normal controls (C). (B) Freshly isolated CD8+ T cells from a T1D patient lost the capacity to discriminate self from nonself. CD8+ and CD4+ T cells were purified from T1D patients, and responses of CD4+ T cells were tested and compared in the presence and absence of CD8+ T cells in a standard self/nonself discrimination assay as described in Methods. Data are shown as mean ± SEM and are representative of 9 of 10 T1D patients tested paired with healthy normal controls. (C) Freshly isolated CD8+ T cells from the majority of the T1D patients tested lost the capacity to discriminate self from nonself in the periphery. Immune responses of purified CD4+ T cells to self-antigen GAD versus to foreign antigen TT were compared with those of CD4+ T cells plus CD8+ T cells in each T1D patient, paired with normal control. Data summarize 10 T1D patients and corresponding controls and are representative of 2 tests for each patient.