CD40L modulates CD4+ T‐cell activation through receptor for activated C kinase 1

Abstract Inhibition of the co‐stimulatory ligand CD40L has shown beneficial effects in many experimental models of autoimmune disease and inflammation. Here, we show that CD40L deficiency in T cells in mice causes a reduction of CD4 + T‐cell activation and specifically a strong reduction in IFN‐γ‐producing Th1 cells. In vitro, we could not reproduce this antigen presenting cell‐dependent effects, but found that T‐cell CD40L affects cell death and proliferation. We identified receptor of activated C kinase, the canonical PKC binding partner and known to drive proliferation and apoptosis, as a mediator of CD40L reverse signaling. Furthermore, we found that CD40L clustering stabilizes IFN‐γ mediated Th1 polarization through STAT1, a known binding partner of receptor of activated C kinase. Together this highlights the importance of both CD40L forward and reverse signaling.