Activin A programs the differentiation of human TFH cells

Crotty and colleagues identify activin A as a regulator of human T FH cell differentiation. The effects of activin A show evolutionary divergence. Follicular helper T cells (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 that regulate the differentiation of human T FH cells. A screen of a human protein library identified activin A as a potent regulator of T FH cell differentiation. Activin A orchestrated the expression of multiple genes associated with the T FH program, independently or in concert with additional signals. T FH cell programming by activin A was antagonized by the cytokine IL-2. Activin A's ability to drive T FH cell differentiation in vitro was conserved in non-human primates but not in mice. Finally, activin-A-induced T FH programming was dependent on signaling via SMAD2 and SMAD3 and was blocked by pharmacological inhibitors.