Abstract
CD4 T cell help plays an important role in promoting CD8 T cell immunity to pathogens. In models of infection with vaccinia virus (VV) and Listeria monocytogenes, CD4 T cell help is critical for the survival of activated CD8 T cells during both the primary and memory recall responses. Still unclear, however, is how CD4 T cell help promotes CD8 T cell survival. In this study, we first showed that CD4 T cell help for the CD8 T cell response to VV infection was mediated by IL-21, a cytokine produced predominantly by activated CD4 T cells, and that direct action of IL-21 on CD8 T cells was critical for the VV-specific CD8 T cell response in vivo. We next demonstrated that this intrinsic IL-21 signaling was essential for the survival of activated CD8 T cells and the generation of long-lived memory cells. We further revealed that IL-21 promoted CD8 T cell survival in a mechanism dependent on activation of the STAT1 and STAT3 pathways and subsequent upregulation of the prosurvival molecules Bcl-2 and Bcl-x(L). These results identify a critical role for intrinsic IL-21 signaling in CD8 T cell responses to an acute viral infection in vivo and may help design effective vaccine strategies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Disease
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Animals
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / pathology*
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CD8-Positive T-Lymphocytes / virology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Survival / immunology
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Cells, Cultured
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Immunologic Memory* / genetics
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Interleukins / deficiency
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Interleukins / genetics
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Interleukins / physiology*
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Mice
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Mice, 129 Strain
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Proto-Oncogene Proteins c-bcl-2 / biosynthesis
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Proto-Oncogene Proteins c-bcl-2 / physiology
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STAT1 Transcription Factor / antagonists & inhibitors
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STAT1 Transcription Factor / physiology
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STAT3 Transcription Factor / antagonists & inhibitors
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STAT3 Transcription Factor / genetics
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Signal Transduction / genetics
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Signal Transduction / immunology*
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Up-Regulation / genetics
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Up-Regulation / immunology
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Vaccinia / genetics
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Vaccinia / immunology*
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Vaccinia / pathology
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bcl-X Protein / antagonists & inhibitors
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bcl-X Protein / biosynthesis
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bcl-X Protein / physiology
Substances
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Bcl2l1 protein, mouse
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Interleukins
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Proto-Oncogene Proteins c-bcl-2
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STAT1 Transcription Factor
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STAT3 Transcription Factor
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Stat1 protein, mouse
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Stat3 protein, mouse
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bcl-X Protein
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interleukin-21