Journal
JOURNAL OF VIROLOGY
Volume 87, Issue 21, Pages 11884-11893Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.01461-13
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Funding
- U.S. National Institutes of Health [AI099753, AI045515, AI083024, AI092212]
- AHA predoctoral fellowship [10PRE4620001]
- NIH predoctoral training grant [T32 HL007910]
- Showalter Trust funds
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Recent evidence has identified the role of granzyme B- and perforin-expressing CD4(+) T cells with cytotoxic potential in antiviral immunity. However, the in vivo cytokine cues and downstream pathways governing the differentiation of these cells are unclear. Here, we have identified that CD4(+) T cells with cytotoxic potential are specifically induced at the site of infection during influenza virus infection. The development of CD4(+) T cells with cytotoxic potential in vivo was dependent on the cooperation of the STAT2-dependent type I interferon signaling and the interleukin-2/interleukin-2 receptor alpha pathway for the induction of the transcription factors T-bet and Blimp-1. We showed that Blimp-1 promoted the binding of T-bet to the promoters of cytolytic genes in CD4(+) T cells and was required for the cytolytic function of the in vitro-and in vivo-generated CD4(+) T cells with cytotoxic potential. Thus, our data define the molecular basis of regulation of the in vivo development of this functionally cytotoxic Th subset during acute respiratory virus infection. The potential implications for the functions of these cells are discussed.
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