A critical function for transforming growth factor-β, interleukin 23 and proinflammatory cytokines in driving and modulating human TH-17 responses

Interleukin 17 (IL-17)-producing T helper 17 cells (T-H-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (T(H)1) and T(H)2 ells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human T-H-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-beta, interleukin 23 (IL-23) and proinflammatory cytokines (IL-1b and IL-6) were all essential for human T-H-17 differentiation. However, individual T-H-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T-H-17 cytokine profile, were differentially modulated by T-H-17-promoting cytokines. Transforming growth factor-beta was critical, and its absence induced a shift from a T-H-17 profile to a T(H)1-like profile. Our results shed new light on the regulation of human T-H-17 differentiation and provide a framework for the global analysis of T helper responses.