Premium
CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury
Author(s) -
Shen Xiuda,
Wang Yue,
Gao Feng,
Ren Feng,
Busuttil Ronald W.,
KupiecWeglinski Jerzy W.,
Zhai Yuan
Publication year - 2009
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.23153
Subject(s) - cd154 , cd40 , inflammation , t cell , liver injury , reperfusion injury , immune system , liver cytology , biology , microbiology and biotechnology , chemistry , immunology , cytotoxic t cell , medicine , endocrinology , ischemia , biochemistry , liver metabolism , in vitro
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 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. (H EPATOLOGY 2009.)