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

Follicular helper T (T FH ) cells are essential for inducing germinal centre (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 signalling 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 signalling and mTOR-HIF1α-metabolic reprogramming coupled with Foxo3 signalling in reprogramming T FH cell differentiation.