The cytokine TGF-β co-opts signaling via STAT3-STAT4 to promote the differentiation of human TFH cells

Understanding the developmental mechanisms of follicular helper T cells (T-FH cells) in humans is relevant to the clinic. However, the factors that drive the differentiation of human CD4(+) helper T cells into T-FH cells remain largely undefined. Here we found that transforming growth factor-beta (TGF-beta) provided critical additional signals for the transcription factors STAT3 and STAT4 to promote initial T-FH differentiation in humans. This mechanism did not appear to be shared by mouse helper T cells. Developing human T-FH cells that expressed the transcriptional repressor Bcl-6 also expressed ROR gamma t, a transcription factor typically expressed by the T(H)17 subset of helper T cells. Our study documents a mechanism by which T-FH cells and T(H)17 cells emerge together in inflammatory environments in humans, as is often observed in many human autoimmune diseases.