Activin A programs human T(FH) cell differentiation

Follicular helper T (T(FH)) cells are CD4(+) T cells specialized in helping B cells and are associated both with protective antibody responses and autoimmune diseases. The promise of targeting T(FH) cells therapeutically has been limited by fragmentary understanding of extrinsic signals regulating human T(FH) cell differentiation. A screen of a human protein library identified activin A as new regulator of T(FH) cell differentiation. Activin A orchestrated expression of multiple T(FH)-associated genes, independently or in concert with additional signals. T(FH) programming by activin A was antagonized by the cytokine IL-2. Activin A’s capacity to drive T(FH) cell differentiation in vitro was conserved for non-human primates but not mice. Finally, activin A-induced T(FH) programming was dependent on SMAD2 and SMAD3 signaling and blocked by pharmacological inhibitors.