title: CD70-driven costimulation induces survival or Fas-mediated apoptosis of T cells depending on antigenic load.
abstract: Apoptosis plays an essential role in the removal of activated CD8 T cells that are no longer required during or postinfection. The Bim-dependent intrinsic pathway of apoptosis removes effector CD8 T cells upon clearance of viral infection, which is driven by withdrawal of growth factors. Binding of Fas ligand to Fas mediates activation-induced T cell death in vitro and cooperates with Bim to eliminate CD8 T cells during chronic infection in vivo, but it is less clear how this pathway of apoptosis is initiated. In this study, we show that the costimulatory TNFR CD27 provides a dual trigger that can enhance survival of CD8 T cells, but also removal of activated CD8 T cells through Fas-driven apoptosis. Using in vitro stimulation assays of murine T cells with cognate peptide, we show that CD27 increases T cell survival after stimulation with low doses of Ag, whereas CD27 induces Fas-driven T cell apoptosis after stimulation with high doses of Ag. In vivo, the impact of constitutive CD70-driven stimulation on the accumulation of memory and effector CD8 T cells is limited by Fas-driven apoptosis. Furthermore, introduction of CD70 signaling during acute infection with influenza virus induces Fas-dependent elimination of influenza-specific CD8 T cells. These findings suggest that CD27 suppresses its costimulatory effects on T cell survival through activation of Fas-driven T cell apoptosis to maintain T cell homeostasis during infection.
authors.affiliation: Department of Experimental Immunology, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Felix M
authors.initials: FM
authors.lastname: Wensveen
authors.forename: Peter-Paul A
authors.initials: PP
authors.lastname: Unger
authors.forename: Natasja A M
authors.initials: NA
authors.lastname: Kragten
authors.forename: Ingrid A M
authors.initials: IA
authors.lastname: Derks
authors.forename: Anja
authors.initials: A
authors.lastname: ten Brinke
authors.forename: Ramon
authors.initials: R
authors.lastname: Arens
authors.forename: Rene A W
authors.initials: RA
authors.lastname: van Lier
authors.forename: Eric
authors.initials: E
authors.lastname: Eldering
authors.forename: Klaas P J M
authors.initials: KP
authors.lastname: van Gisbergen
mesh_terms: D000818:Animals; D000941:Antigens / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D053282:CD27 Ligand / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002908:Chronic Disease; D007156:Immunologic Memory / Q000235:genetics; D007239:Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D010455:Peptides / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D019014:fas Receptor / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D053282:CD27 Ligand; C491899:Fas protein, mouse; D008565:Membrane Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D019014:fas Receptor