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

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. An overview of our proposed signaling cascade of CD40L reverse signaling. Binding of CD40L on the CD4+ T cell by CD40 results in an increase in CD4+ T cell proliferation and survival. We identified receptor for activated C kinase 1 (RACK1) as a novel bindingpartner of CD40L. Furthermore, CD40L activation stabilizes Th1 polarizion through increased STAT1 signaling, a known binding partner of RACK1, suggesting a further role of CD40L in polarizing CD4+ T cells.