HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes.
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.
Jiang
Hong
H
Department of Medicine, Naomi Berrie Diabetes Center (NBDC), Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA. hj4@columbia.edu
Canfield
Steve M
SM
Gallagher
Mary P
MP
Jiang
Hong H
HH
Jiang
Yihua
Y
Zheng
Zongyu
Z
Chess
Leonard
L
D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D002460:Cell Line; D018834:Chaperonin 60 / Q000276:immunology; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000276:immunology; D006680:HLA Antigens / Q000502:physiology*; D015395:Histocompatibility Antigens Class I / Q000502:physiology*; D006801:Humans; D008969:Molecular Sequence Data; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D000097625:HLA-E Antigens
D018834:Chaperonin 60; D006680:HLA Antigens; D015395:Histocompatibility Antigens Class I; D000097625:HLA-E Antigens