Differentiation of IL-17-producing effector and regulatory human t cells from lineage-committed naive precursors

A subset of human regulatory T cells (Tregs) secretes IL-17 and thus resembles Th17 effector cells. How IL-17⁺ Tregs differentiate from naive precursors remains unclear. In this study, we show that IL-17-producing T cells can differentiate from CCR6⁺ naive T cell precursors in the presence of IL-2, IL-1β, TGF-β, and IL-23. CCR6⁺ naive T cells are present in adult peripheral and umbilical cord blood and in both conventional T naive and FOXP3⁺ naive Treg subsets. IL-17⁺ cells derived from CCR6⁺ naive Tregs (referred to as IL-17 ⁺ Tregs) 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⁺ naive 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.