Abstract
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-1β, but not IL-6. “IL-17 potential” is restricted to population III (CD4+CD25hiCD127loCD45RA−) 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.
Highlights
Physiological maintenance of peripheral tolerance is critically dependent on a population of circulating cells committed to suppressor function
We confirm that a proportion of the human Treg-cell pool in circulation can be induced in vitro to produce IL-17 when activated in the presence of IL-1β, in a STAT3-dependent manner
We further demonstrate that “IL-17 potential” is isolated to population III (CD4+CD25++CD127loCD45RA−) Treg cells and that this effect is almost exclusively restricted to a subpopulation within population III that expresses the NK-cell marker CD161
Summary
Physiological maintenance of peripheral tolerance is critically dependent on a population of circulating cells committed to suppressor function. Administration of Treg cells in murine models controls experimental allergic [7] and autoimmune diseases [8] and can prevent rejection of allografts [9] while in borderline or acutely rejecting human renal and liver transplant specimens, Treg-cell numbers correlate positively with better outcomes [10, 11]. These properties, together with the observation that human Treg cells can be expanded ex vivo, either polyclonally [12,13] or for a given specificity [14], make Treg cells ideal candidates for tolerance-inducing cell therapy in human autoimmune diseases and transplantation [15]. Small-scale trials have demonstrated beneficial outcomes in the prevention or treatment of postbone marrow transplantation human graft versus host disease [16]
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