The differentiation of human TH-17 cells requires transforming growth factor-β and induction of the nuclear receptor RORγt

T(H)-17 cells are interleukin 17 (IL-17)-secreting CD4(+) T helper cells involved in autoimmune disease and mucosal immunity. In naive CD4(+) T cells from mice, IL-17 is expressed in response to a combination of IL-6 or IL-21 and transforming growth factor-beta (TGF-beta) and requires induction of the nuclear receptor ROR gamma t. It has been suggested that the differentiation of human TH-17 cells is independent of TGF-beta and thus differs fundamentally from that in mice. We show here that TGF-beta, IL-1 beta and IL-6, IL-21 or IL-23 in serum-free conditions were necessary and sufficient to induce IL-17 expression in naive human CD4(+) T cells from cord blood. TGF-beta upregulated ROR gamma t expression but simultaneously inhibited its ability to induce IL-17 expression. Inflammatory cytokines relieved this inhibition and increased ROR gamma t-directed IL-17 expression. Other gene products detected in T(H)-17 cells after ROR gamma t induction included the chemokine receptor CCR6, the IL-23 receptor, IL-17F and IL-26. Our studies identify ROR gamma t as having a central function in the differentiation of human TH-17 cells from naive CD4(+) T cells and suggest that similar cytokine pathways are involved in this process in mice and humans.