CD4 T Cells Promote Tissue Inflammation via CD40 Signaling Without De Novo Activation in a Murine Model of Liver Ischemia/Reperfusion Injury

Although the role of CD4 T cells in tissue inflammation and organ injury resulting from ischemia and reperfusion injury (IRI) has been well documented, it remains unclear how CD4 T cells are activated and function in the absence of a specific antigen (Ag). We used a murine liver warm IRI model to determine first whether de novo Ag-specific CD4 T cell activation was required and then what its functional mechanism was. The critical role of CD4 T cells in liver immune activation against ischemia and reperfusion (IR) was confirmed in CD4 knockout mice and CD4 depleted wild-type mice. Interestingly, the inhibition of CD4 T cell activation without target cell depletion failed to protect livers against IRI, and this suggested that T cells function in liver IRI without, Ag-specific de novo activation. To dissect the T cell functional mechanism, we found that CD154 blockade, but not interferon gamma (IFN-gamma) neutralization, inhibited local immune activation and protected livers from IRI. Furthermore, agonist anti-CD40 antibodies restored liver IRI in otherwise protected CD4-deficient hosts. Finally, fluorescence-activated cell sorting analysis of liver CD4 T cells revealed the selective infiltration of effector cells, which constitutively expressed a higher level of CD 154 in comparison with their peripheral counterparts. IR triggered a significant liver increase in CD40 expression but not CD154 expression, and macrophages responded to toll-like receptor 4 and type I IFN stimulation to up-regulate CD40 expression. Conclusion: These novel findings provide evidence that CD4 T cells function in liver IRI via CD 154 without de novo Ag-specific activation, and innate immunity-induced CD40 up-regulation may trigger the engagement of CD154-CD40 to facilitate tissue inflammation and injury. (HEPATOLOGY 2009; 50:1537-1546.)