Activin A programs the differentiation of human [T.sub.FH] cells

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