CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury

Xiuda Shen, Yue Wang, Feng Gao, Feng Ren, Ronald W. Busuttil, Jerzy W. Kupiec-Weglinski, Yuan Zhai

Research output: Contribution to journalArticlepeer-review

82 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1537-1546
Number of pages10
JournalHepatology
Volume50
Issue number5
DOIs
StatePublished - 2009

ASJC Scopus subject areas

  • Hepatology

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