期刊
EUROPEAN JOURNAL OF IMMUNOLOGY
卷 43, 期 8, 页码 2043-2054出版社
WILEY-BLACKWELL
DOI: 10.1002/eji.201243296
关键词
Conversion; Human; Regulatory T (Treg) cells; STAT3; Th17
类别
资金
- National Institute for Health Research
- Medical Research Council
- Academy of Medical Sciences/Wellcome Trust
- Wellcome Trust
- British Heart Foundation
- Guy's and St Thomas' Charity
- Arthritis Research UK
- ONE study
- Department of Health via the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award
- King's College Hospital NHS Foundation Trust
- MRC [MR/K025538/1, G0400197, G0500429] Funding Source: UKRI
- British Heart Foundation [RG/08/005/25303] Funding Source: researchfish
- Cancer Research UK
- Versus Arthritis [19307] Funding Source: researchfish
- Medical Research Council [MR/J006742/1, G0400197, MR/K025538/1, G0500429] Funding Source: researchfish
- National Institute for Health Research [DRF-2009-02-22, CL-2008-17-003] Funding Source: researchfish
- National Institutes of Health Research (NIHR) [DRF-2009-02-22] Funding Source: National Institutes of Health Research (NIHR)
Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are plastic, and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1, but not IL-6. IL-17 potential is restricted to population III (CD4(+)CD25(hi)CD127(lo)CD45RA(-)) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17. Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites. As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.
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