Published online before print May 3, 2007

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Copyright © 2007 American Society for Investigative Pathology
American Journal of Pathology, doi:10.2353/ajpath.2007.061099

Accepted for publication March 27, 2007.

Article

CD8⁺ T Cells Promote Inflammation and Apoptosis in the Liver after Sepsis. Role of Fas-FasL

Doreen E. Wesche-Soldato^*, Chun-Shiang Chung^*, Stephen H. Gregory, Thais P. Salazar-Mather, Carol A. Ayala^*, and Alfred Ayala^*@

From Surgical Research,* the Department of Surgery, Brown University School of Medicine and Rhode Island Hospital, Providence; and the Departments of Medicine and Molecular Microbiology and Immunology, Brown University School of Medicine, Providence, Rhode Island

^@ To whom correspondence should be addressed. E-mail: aayala{at}lifespan.org.

	Abstract

Although studies blocking the Fas pathway indicate it can decrease organ damage while improving septic (cecal ligation and puncture, CLP) mouse survival, little is known about how Fas-Fas ligand (FasL) interactions mediate this protection at the tissue level. Here, we report that although Fas expression on splenocytes and hepatocytes is up-regulated by CLP and is inhibited by in vivo short interfering RNA, FasL as well as the frequency of CD8⁺ T cells are differentially altered by sepsis in the spleen (no change in FasL, decreased percentage of CD8⁺ and CD4⁺ T cells) versus the liver (increased FasL expression on CD8⁺ T cells and increase in percentage/number). Adoptive transfer of CLP FasL^+/+ versus FasL^-/- mouse liver CD8⁺ T cells to severe combined immunodeficient or RAG1^-/- recipient mice indicated that these cells could induce inflammation. The FasL-mediated cytotoxic capacity of these septic mouse liver CD8⁺ T cells was shown by their ability to damage directly cultured hepatocytes. Finally, although CD8^-/- mice exhibited a reduction in both CLP-induced liver active caspase-3 staining and blood interleukin-6 levels, only FasL^-/- (but not CD8^-/-) protected the septic mouse spleen from increasing apoptosis. Thus, although truncating Fas-FasL signaling ameliorates many untoward effects of sepsis, the pathological mode of action is distinct at the tissue level.

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