Shen Xiuda, Wang Yue, Gao Feng, Ren Feng, Busuttil Ronald W, Kupiec-Weglinski Jerzy W, Zhai Yuan
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.
Hepatology. 2009 Nov;50(5):1537-46. doi: 10.1002/hep.23153.
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.
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.
尽管CD4 T细胞在缺血再灌注损伤（IRI）导致的组织炎症和器官损伤中的作用已得到充分证实，但在缺乏特异性抗原（Ag）的情况下，CD4 T细胞如何被激活以及发挥功能仍不清楚。我们使用小鼠肝脏热缺血再灌注模型，首先确定是否需要从头进行抗原特异性CD4 T细胞激活，然后确定其功能机制是什么。在CD4基因敲除小鼠和CD4耗竭的野生型小鼠中证实了CD4 T细胞在肝脏针对缺血再灌注（IR）的免疫激活中的关键作用。有趣的是，在不消耗靶细胞的情况下抑制CD4 T细胞激活并不能保护肝脏免受IRI的影响，这表明T细胞在肝脏IRI中发挥作用，而无需抗原特异性的从头激活。为了剖析T细胞的功能机制，我们发现阻断CD154而非中和干扰素γ（IFN-γ）可抑制局部免疫激活并保护肝脏免受IRI的影响。此外，激动剂抗CD40抗体可恢复原本受到保护的CD4缺陷宿主中的肝脏IRI。最后，对肝脏CD4 T细胞进行荧光激活细胞分选分析发现，效应细胞选择性浸润，与外周对应细胞相比，其组成性表达更高水平的CD154。IR引发肝脏中CD40表达显著增加，但CD154表达未增加，巨噬细胞对Toll样受体4和I型干扰素刺激作出反应，上调CD40表达。
这些新发现提供了证据，表明CD4 T细胞在肝脏IRI中通过CD154发挥作用，而无需从头进行抗原特异性激活，并且先天免疫诱导的CD40上调可能触发CD154-CD40的相互作用，以促进组织炎症和损伤。
