A TRAF-like motif of ICOS controls development of germinal center T follicular helper cells via TBK1

Inducible costimulator (ICOS) signaling fuels the stepwise development of T follicular helper (T(FH)) cells. However, a signaling pathway unique to ICOS has not been identified. We show that TANK-binding kinase 1 (TBK1) associates with ICOS via a conserved motif, IProx, which shares homology with tumor necrosis factor receptor (TNFR)-associated factors, TRAF2 and TRAF3. Disruption of this motif abolishes the association with TBK1, thus identifying a TBK1-binding consensus. Mutation of this motif in ICOS, or depletion of TBK1 in T cells severely impaired the differentiation of germinal center (GC) T(FH), B cell and antibody responses, but was dispensable for early T(FH) differentiation. These results reveal a novel ICOS-TBK1 signaling pathway that specifies GC T(FH) cell commitment.