Viral FLIP impairs survival of activated T cells and generation of CD8+ T cell memory.
Viral FLIPs (vFLIPs) interfere with apoptosis signaling by death-domain-containing receptors in the TNFR superfamily (death receptors). In this study, we show that T cell-specific transgenic expression of MC159-vFLIP from the human Molluscum contagiosum virus blocks CD95-induced apoptosis in thymocytes and peripheral T cells, but also impairs postactivation survival of in vitro activated primary T cells despite normal early activation parameters. MC159 vFLIP impairs T cell development to a lesser extent than does Fas-associated death domain protein deficiency or another viral FLIP, E8. In the periphery, vFLIP expression leads to a specific deficit of functional memory CD8(+) T cells. After immunization with a protein Ag, Ag-specific CD8(+) T cells initially proliferate, but quickly disappear and fail to produce Ag-specific memory CD8(+) T cells. Viral FLIP transgenic mice exhibit impaired CD8(+) T cell responses to lymphocytic choriomeningitis virus and Trypanosoma cruzi infections, and a specific defect in CD8(+) T cell recall responses to influenza virus was seen. These results suggest that vFLIP expression in T cells blocks signals necessary for the sustained survival of CD8(+) T cells and the generation of CD8(+) T cell memory. Through this mechanism, vFLIP proteins expressed by T cell tropic viruses may impair the CD8(+) T cell immune responses directed against them.
Wu
Zhengqi
Z
Immunoregulation Unit, Autoimmunity Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
Roberts
Margaret
M
Porter
Melissa
M
Walker
Fabianne
F
Wherry
E John
EJ
Kelly
John
J
Gadina
Massimo
M
Silva
Elisabeth M
EM
DosReis
George A
GA
Lopes
Marcela F
MF
O'Shea
John
J
Leonard
Warren J
WJ
Ahmed
Rafi
R
Siegel
Richard M
RM
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000637:transplantation; D002455:Cell Division / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D014355:Chagas Disease / Q000235:genetics / Q000276:immunology; D004268:DNA-Binding Proteins / Q000502:physiology; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D007156:Immunologic Memory / Q000235:genetics; D016130:Immunophenotyping; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology*; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008894:Milk Proteins; D008977:Molluscum contagiosum virus / Q000276:immunology; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D050799:STAT5 Transcription Factor; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D015534:Trans-Activators / Q000502:physiology; D014349:Trypanosoma cruzi / Q000276:immunology; D014764:Viral Proteins / Q000096:biosynthesis / Q000235:genetics / Q000633:toxicity*; D019014:fas Receptor / Q000235:genetics
D004268:DNA-Binding Proteins; D018984:Epitopes, T-Lymphocyte; D008894:Milk Proteins; D018124:Receptors, Tumor Necrosis Factor; D050799:STAT5 Transcription Factor; D015534:Trans-Activators; D014764:Viral Proteins; D019014:fas Receptor; C481275:viral FLIP protein, Human herpesvirus 8