A TRAF-like motif of the inducible costimulator ICOS controls development of germinal center TFH cells via the kinase TBK1

Signaling via the inducible costimulator ICOS drives the stepwise development of follicular helper T cells. Kong and colleagues describe an ICOS–kinase TBK1 signaling pathway that specifies the commitment of these cells. Signaling via the inducible costimulator ICOS fuels the stepwise development of follicular helper T cells (T FH cells). However, a signaling pathway unique to ICOS has not been identified. We found here that the kinase TBK1 associated with ICOS via a conserved motif, IProx, that shares homology with the tumor-necrosis-factor receptor (TNFR)-associated factors TRAF2 and TRAF3. Disruption of this motif abolished the association of TBK1 with ICOS, TRAF2 and TRAF3, which identified a TBK1-binding consensus. Alteration of this motif in ICOS or depletion of TBK1 in T cells severely impaired the differentiation of germinal center (GC) T FH cells and the development of GCs, interfered with B cell differentiation and disrupted the development of antibody responses, but the IProx motif and TBK1 were dispensable for the early differentiation of T FH cells. These results reveal a previously unknown ICOS-TBK1 signaling pathway that specifies the commitment of GC T FH cells.