Abstract
Agonistic anti-CD137 mAbs either positively or negatively regulate T cell function. When administered at the beginning of lymphocytic choriomeningitis virus Armstrong infection anti-CD137 induced immunosuppression and T cell deletion, and in the case of influenza infection led to increased mortality. In contrast, 72 h delay in anti-CD137 treatment led to an enhanced virus-specific CD8 T cell response and rapid viral clearance. Virus-specific CD8 T cells in anti-CD137-injected mice rapidly upregulate Fas expression, and although necessary, was insufficient to induce CD8 T cell deletion. Strikingly, CD137 signaling in T cells was found to be insufficient to induce suppression or deletion. Rather, immunosuppression and T cell deletion was only observed if CD137 signals were provided to T cells and dendritic cells (DCs). In vitro CD137 crosslinking in DCs led to phosphorylation of Stat3, and importantly, anti-CD137 treatment of lymphocytic choriomeningitis virus Armstrong infected Stat3 conditional knock-out mice induced neither immune suppression or T cell deletion. Taken together, these data suggest that CD137 signaling in DCs can regulate CD8 T cell survival through a Stat3 and Fas-mediated pathway.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adoptive Transfer
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Animals
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / transplantation
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CD8-Positive T-Lymphocytes / virology
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Cell Death / genetics
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Cell Death / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Dendritic Cells / immunology*
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Dendritic Cells / metabolism*
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Dendritic Cells / virology
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Epitopes, T-Lymphocyte / immunology
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Fas Ligand Protein
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Female
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology*
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Lymphocyte Depletion
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Lymphocytic Choriomeningitis / immunology
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Lymphocytic Choriomeningitis / metabolism
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Lymphocytic Choriomeningitis / virology
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Lymphocytic choriomeningitis virus / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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STAT3 Transcription Factor / metabolism
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STAT3 Transcription Factor / physiology*
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Signal Transduction / genetics
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Signal Transduction / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / deficiency
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / immunology
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Tumor Necrosis Factor Receptor Superfamily, Member 9 / physiology*
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fas Receptor / physiology
Substances
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Epitopes, T-Lymphocyte
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Fas Ligand Protein
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STAT3 Transcription Factor
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Stat3 protein, mouse
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Tumor Necrosis Factor Receptor Superfamily, Member 9
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fas Receptor