CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner.
Bottom Line: 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.
Affiliation: Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK. firstname.lastname@example.orgShow MeSH
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Mentions: It has been shown both in murine models and in man that Treg cells are plastic. In order to identify the population of Treg cells responsible for the conversion to IL-17-producing cells and the mechanisms behind this event, freshly isolated bead-enriched “whole” human Treg cells (CD4+CD25+) were initially activated in vitro in the presence of IL-1β, as previously reported [25,26], and/or IL-2. We observed that Treg cells produced IL-17 when in the presence of IL-1β and the highest levels were found when IL-2 was further added to the culture (Fig. 1A), in part due to IL-2-mediated increased expression of IL-1R1 (Supporting Information Fig. 1), as previously shown . The increased IL-17 mediated by IL-1β was confirmed with intracellular staining (ICS) and was accompanied by a reduction in FOXP3 (Fig. 1B and C). A negative correlation between the percentage of IL-17 and FOXP3 single-positive cells was observed following activation of Treg cells in the presence of IL-1β plus IL-2 (r2 = 0.79, p < 0.05) (Fig. 1C). The presence of IL-2, however, maintained a higher percentage of FOXP3+ cells in ex vivo activated Treg cells but the addition of IL-1β antagonized this effect (Fig. 1C). The conversion of Treg cells to Th17 cells, rather than outgrowth of a contaminating population, was suggested by repeated observation of cells that were double positive for both FOXP3 and IL-17 (Fig. 1D, top panel), plus a kinetic transition through a double-positive phase (Fig. 1D, lower panel and Supporting Information Fig. 2), indicative of a transitional stage. In the double-positive population, FOXP3 levels were lower in those cells expressing higher IL-17 levels (Fig. 1D).
Affiliation: Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK. email@example.com