CD8+ T cells promote inflammation and apoptosis in the liver after sepsis: role of Fas-FasL.
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.
Wesche-Soldato
Doreen E
DE
Surgical Research, Aldrich 227, Rhode Island Hospital, Providence, RI 02903, USA.
Chung
Chun-Shiang
CS
Gregory
Stephen H
SH
Salazar-Mather
Thais P
TP
Ayala
Carol A
CA
Ayala
Alfred
A
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology*; D053222:Fas Ligand Protein / Q000502:physiology*; D006505:Hepatitis / Q000276:immunology / Q000378:metabolism*; D007249:Inflammation / Q000276:immunology; D008099:Liver / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D018805:Sepsis / Q000276:immunology* / Q000473:pathology; D015398:Signal Transduction; D013154:Spleen / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000502:physiology*
D053222:Fas Ligand Protein; D019014:fas Receptor