The Hippo kinase MST1 negatively regulates the differentiation of follicular helper T cells

Follicular helper T (T_FH ) cells are essential for inducing germinal center (GC) reactions to mediate humoral adaptive immunity and Antiviral effects, but the mechanisms of T_FH cell differentiation remain unclear. Here, we found that the Hippo kinase MST1 is critical for T_FH cell differentiation, GC formation and antibody production under steady-state conditions and viral Infection. MST1 deficiency intrinsically enhanced T_FH cell differentiation and GC reactions in vivo and in vitro. Mechanistically, mTOR and HIF1α signaling is involved in glucose metabolism and increased glycolysis and decreased OXPHOS, which are critically required for MST1 deficiency-directed T_FH cell differentiation. Moreover, upregulated Foxo3 expression is critically responsible for T_FH cell differentiation induced by Mst1^-/- . Thus, our findings identify a previously unrecognized relationship between Hippo kinase MST1 signaling and mTOR-HIF1α-metabolic reprogramming coupled with Foxo3 signaling in reprogramming T_FH cell differentiation.

GC reaction; T cell differentiation; TFH; follicular helper T cells; infectious diseases; kinase MST1; metabolism; virus infection.