Regulation of Fas ligand-induced apoptosis by TNF.
Fas ligand (FasL, CD95L) expression helps control inflammatory reactions in immune privileged sites such as the eye. Cellular activation is normally required to render lymphoid cells sensitive to FasL-induced death; however, both activated and freshly isolated Fas(+) lymphoid cells are efficiently killed in the eye. Thus, we examined factors that might regulate cell death in the eye. TNF levels rapidly increased in the eye after the injection of lymphoid cells, and these cells underwent apoptosis within 24 h. Coinjection of anti-TNF Ab with the lymphoid cells blocked this cell death. Furthermore, TNFR2(-/-) T cells did not undergo apoptosis in the eyes of normal mice, while normal and TNFR1(-/-) T cells were killed by apoptosis. In vitro, TNF enhanced the Fas-mediated apoptosis of unactivated T cells through decreased intracellular levels of FLIP and increased production of the pro-apoptotic molecule Bax. This effect was mediated through the TNFR2 receptor. In vivo, intracameral injection of normal or TNFR1(-/-) 2,4,6-trinitrophenyl-coupled T cells into normal mice induced immune deviation, but TNFR2(-/-) 2,4,6-trinitrophenyl-coupled T cells were ineffective. Collectively, our results provide evidence of a role for the p75 TNFR in cell death in that TNF signaling through TNFR2 sensitizes lymphoid cells for Fas-mediated apoptosis. We conclude that there is complicity between apoptosis and elements of the inflammatory response in controlling lymphocyte function in immune privileged sites.
Elzey
B D
BD
Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO 63110, USA.
Griffith
T S
TS
Herndon
J M
JM
Barreiro
R
R
Tschopp
J
J
Ferguson
T A
TA
D000818:Animals; D000867:Anterior Chamber / Q000276:immunology*; D015703:Antigens, CD / Q000235:genetics / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D001813:Blood-Retinal Barrier; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D005136:Eye Proteins / Q000494:pharmacology / Q000502:physiology*; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000276:immunology*; D006241:Haptens; D047908:Intracellular Signaling Peptides and Proteins; D008214:Lymphocytes / Q000166:cytology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010853:Picryl Chloride; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D016176:T-Lymphocyte Subsets / Q000166:cytology* / Q000637:transplantation; D018418:Th2 Cells / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*; D051028:bcl-2-Associated X Protein; D019014:fas Receptor / Q000502:physiology*
D015703:Antigens, CD; C494827:Bax protein, mouse; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D002352:Carrier Proteins; C506387:Cflar protein, mouse; D005136:Eye Proteins; D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D006241:Haptens; D047908:Intracellular Signaling Peptides and Proteins; D008562:Membrane Glycoproteins; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; D010853:Picryl Chloride