Differentiation of IL-17–Producing Effector and Regulatory Human T Cells from Lineage-Committed Naive Precursors

Abstract

A subset of human regulatory T cells (Tregs) secretes IL-17 and thus resembles Th17 effector cells. How IL-17+Treg cells differentiate from naïve precursors remains unclear. Here, we show that IL-17-producing T-cells can differentiate from CCR6+ naïve T cell precursors in the presence of IL-2, IL-1β, TGF-β, and IL-23. CCR6+ naïve T cells are present in adult peripheral and umbilical cord blood and in both conventional T naïve (TN) and FOXP3+ naïve Treg (TNreg) subsets. IL-17+ cells derived from CCR6+ TNreg cells (referred to as IL-17+Treg) express FOXP3, but not HELIOS, another Treg-associated transcription factor, and these cells display suppressor capacity and a surface phenotype resembling memory Tregs. Remarkably, the IL-17+Treg compartment was preferentially reduced relative to the canonical Th17 and Treg compartments in a subset of HIV+ subjects, suggesting a specific perturbation of this subset during the course of disease. Our findings that CCR6+ naïve precursors contain a predetermined reservoir to replenish IL-17-secreting cells, may have implications in balancing the Th17 and IL-17+Treg compartments that are perturbed during HIV infection and potentially in other inflammatory diseases.

CCR6/CCL20 chemokine axis in human immunodeficiency virus immunity and pathogenesis

“…Most of these cells were, in fact, CCR6 + precursors of T H 17 and T H 17-regulatory cells [50,51]. In HIV-infected individuals on ART, T H 17-regulatory cells (IL-17 + T reg cells) were found to be preferentially reduced compared with T reg cells [51].…”

“…Most of these cells were, in fact, CCR6 + precursors of T H 17 and T H 17-regulatory cells [50,51]. In HIV-infected individuals on ART, T H 17-regulatory cells (IL-17 + T reg cells) were found to be preferentially reduced compared with T reg cells [51]. These observations suggest that CCR6 is a marker of this precursor population and that they may be preferentially infected in HIV infections, leading to failure of full T H 17 polarization and, therefore, decreased T H 17 cells in HIV patients [48].…”

(Compl)Ex-Th17–Tregcell inter-relationship

“…Similar data by Mercer et al substantiate the selective differentiation of IL17 C FoxP3 C T cells from lineage-committed naive CCR6 C FoxP3 C precursors. 17 Opposite, Th17 cells can convert to IL17 C FoxP3 C cells and exTh17-FoxP3 C cells. Whether IL17 C FoxP3 C cells represent a stable lineage or a transient state remains to be determined.…”

Signal Strength and Metabolic Requirements Control Cytokine-Induced Th17 Differentiation of Uncommitted Human T Cells

“…Precommitted Th17 cells are already present in the thymus of humans and mice (7,12). Specifically, in humans it was documented by several different groups that Th17 cells could be generated from precommitted precursors with Th17-promoting cytokines, whereas uncommitted T cells failed to produce IL-17 (7,(13)(14)(15)(16). In other reports that defined the requirements of human Th17 cell differentiation, precommitted and uncommitted naive T cells were not analyzed separately.…”