title: CD4 T cells promote tissue inflammation via CD40 signaling without de novo activation in a murine model of liver ischemia/reperfusion injury.
abstract: 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 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.
  
  
  CONCLUSIONS
  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.
authors: Dumont-UCLA Transplant Center, Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine, University of California-Los Angeles, Los Angeles, CA, USA.
authors: Xiuda
authors: X
authors: Shen
authors: Yue
authors: Y
authors: Wang
authors: Feng
authors: F
authors: Gao
authors: Feng
authors: F
authors: Ren
authors: Ronald W
authors: RW
authors: Busuttil
authors: Jerzy W
authors: JW
authors: Kupiec-Weglinski
authors: Yuan
authors: Y
authors: Zhai
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000235:genetics / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D006505:Hepatitis / Q000378:metabolism / Q000473:pathology*; D007371:Interferon-gamma / Q000378:metabolism; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008819:Mice, Nude; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*; D015398:Signal Transduction / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D015704:CD4 Antigens; D019013:CD40 Antigens; D016827:CD8 Antigens; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D023201:CD40 Ligand; D007371:Interferon-gamma