TY - JOUR
T1 - CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury
AU - Shen, Xiuda
AU - Wang, Yue
AU - Gao, Feng
AU - Ren, Feng
AU - Busuttil, Ronald W.
AU - Kupiec-Weglinski, Jerzy W.
AU - Zhai, Yuan
PY - 2009
Y1 - 2009
N2 - Although the role ofCD4Tcells 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 γ (IFN-γ) 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 CD154 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 CD154 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.
AB - Although the role ofCD4Tcells 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 γ (IFN-γ) 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 CD154 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 CD154 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.
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U2 - 10.1002/hep.23153
DO - 10.1002/hep.23153
M3 - Article
C2 - 19670423
AN - SCOPUS:72949086418
VL - 50
SP - 1537
EP - 1546
JO - Hepatology
JF - Hepatology
SN - 0270-9139
IS - 5
ER -