TGF-β co-opts STAT3-STAT4 signaling to promote human T follicular helper cell differentiation

Understanding the developmental mechanisms of T follicular helper (T(FH)) cells in humans is a highly relevant topic to clinic. However, factors that drive human CD4(+) helper T (T(H)) cell differentiation program towards T(FH) cells remain largely undefined. Here we show that TGF-β provides critical additional signals for the transcription factors STAT3 and STAT4 to promote the initial T(FH) differentiation programs in humans. This mechanism does not appear to be shared with mouse T(H) cells. The developing human Bcl-6(+) T(FH) cells also expressed RORγt, a transcription factor typically expressed by T(H)17 cells. Our study documents a mechanism by which T(FH) and T(H)17 cells co-emerge in inflammatory environments in humans, as often observed in many human autoimmune diseases.