The posttraumatic response of CD4+ regulatory T cells is modulated by direct cell-cell contact via CD40L- And P-selectin-dependent pathways

cD4+ Foxp3+ regulatory t cells (cD4+ tregs) are important for the posttraumatic anti-inflammatory host response. as described previously, platelets are able to modulate cD4+ treg activity in a reciprocally activating interaction following injury. the underlying mechanisms of the posttraumatic interaction between platelets and cD4+ tregs remain unclear. We investigated the potential influence of cD40l and p-selectin, molecules known to be involved in direct cell contact of these cell types. in a murine burn injury model, the potential interaction pathways were addressed using cD40l- and p-selectin-deficient mice. Draining lymph nodes were harvested following trauma (1 h) and following a sham procedure. Early rapid activation of cD4+ tregs was assessed by phospho-flow cytometry (signaling molecules (p)pkc-θ and (p)Zap-70). platelet function was analyzed performing rotational thromboelastometry (rotEM). We hypothesized that disruption of the direct cell-cell contact via cD40l and p-selectin would affect posttraumatic activation of cD4+ tregs and influence the hemostatic function of platelets. indeed, while injury induced early activation of cD4+ tregs in wild-type mice (Zap-70: p = 0.13, pZap-70: p < 0.05, pkc-θ: p < 0.05, ppkc-θ: p < 0.05), disruption of cD40l-dependent interaction (Zap-70: p = 0.57, pZap-70: p = 0.68, pkc-θ: p = 0.68, ppkc-θ: p = 0.9) or p-selectin-dependent interaction (Zap-70: p = 0.78, pZap-70: p = 0.58, pkc-θ: p = 0.81, ppkc-θ: p = 0.73) resulted in reduced posttraumatic activation. Furthermore, hemostatic function was impaired towards hypocoagulability in either deficiency. our results suggest that the posttraumatic activation of cD4+ tregs and hemostatic function of platelets are affected by direct cell-cell-signaling via cD40l and p-selectin.