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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Animals
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Antigens / genetics
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Antigens / immunology*
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Antigens / metabolism
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Apoptosis / genetics
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Apoptosis / immunology*
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Apoptosis Regulatory Proteins / genetics
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Apoptosis Regulatory Proteins / immunology
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Apoptosis Regulatory Proteins / metabolism
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Bcl-2-Like Protein 11
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CD27 Ligand / genetics
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CD27 Ligand / immunology*
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CD27 Ligand / metabolism
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Cell Survival / genetics
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Cell Survival / immunology
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Chronic Disease
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Immunologic Memory / genetics
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Infections / genetics
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Infections / immunology
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Infections / metabolism
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Membrane Proteins / genetics
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Peptides / genetics
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Peptides / immunology
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Peptides / metabolism
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / immunology
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Proto-Oncogene Proteins / metabolism
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Signal Transduction*
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / genetics
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 7 / metabolism
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fas Receptor / genetics
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fas Receptor / immunology*
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fas Receptor / metabolism
Substances
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Antigens
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Apoptosis Regulatory Proteins
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Bcl-2-Like Protein 11
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Bcl2l11 protein, mouse
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CD27 Ligand
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Fas protein, mouse
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Membrane Proteins
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Peptides
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Proto-Oncogene Proteins
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Tumor Necrosis Factor Receptor Superfamily, Member 7
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fas Receptor