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+ 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.