Intrinsic IL-21 signaling is critical for CD8 T cell survival and memory formation in response to vaccinia viral infection.
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.
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Patricia
P
Novy
Xiaopei
X
Huang
Warren J
WJ
Leonard
Yiping
Y
Yang
D000208:Acute Disease; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology* / Q000821:virology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000276:immunology; D002478:Cells, Cultured; D007156:Immunologic Memory / Q000235:genetics; D007378:Interleukins / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D051379:Mice; D057507:Mice, 129 Strain; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000502:physiology; D050794:STAT1 Transcription Factor / Q000037:antagonists & inhibitors / Q000502:physiology; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D015854:Up-Regulation / Q000235:genetics / Q000276:immunology; D014615:Vaccinia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051020:bcl-X Protein / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology; D000098546:Interleukin-21
C494812:Bcl2l1 protein, mouse; D007378:Interleukins; D019253:Proto-Oncogene Proteins c-bcl-2; D050794:STAT1 Transcription Factor; D050796:STAT3 Transcription Factor; C494080:Stat1 protein, mouse; C494087:Stat3 protein, mouse; D051020:bcl-X Protein; D000098546:Interleukin-21
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