We found upregulation of expression of the microRNA miR-155 in primary effector and effector memory CD8+ T cells, but low miR-155 expression in naive and central memory cells. Antiviral CD8+ T cell responses and viral clearance were impaired in miR-155-deficient mice, and this defect was intrinsic to CD8+ T cells, as miR-155-deficient CD8+ T cells mounted greatly diminished primary and memory responses. Conversely, miR-155 overexpression augmented antiviral CD8+ T cell responses in vivo. Gene-expression profiling showed that miR-155-deficient CD8+ T cells had enhanced type I interferon signaling and were more susceptible to interferon's antiproliferative effect. Inhibition of the type I interferon–associated transcription factors STAT1 or IRF7 resulted in enhanced responses of miR-155-deficient CD8+ T cells in vivo. We have thus identified a previously unknown role for miR-155 in regulating responsiveness to interferon and CD8+ T cell responses to pathogens in vivo.
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We thank W. Gerhard (Wistar Institute) for influenza virus strain A/Puerto Rico/8/34; D. Topham (University of Rochester) for influenza virus strain A/WSN/33 expressing OVA(257–264); H. Shen (University of Pennsylvania) for OVA-expressing L. monocytogenes; E. Vigorito (Babraham Institute) for control and miR-155-expressing MigR1 vectors; G. Takaesu (Keio University) for STAT1YF-IRES-GFP-pMX (DN-STAT1) and control retroviruses; B. tenOever (Mount Sinai School of Medicine) for DN-IRF7 plasmid; P. Marack (University of Colorado Health Sciences Center) for the MSCV-IRES-Thy-1.1 vector; and the Penn Molecular Profiling facility at the University of Pennsylvania for microarray assays. Some of this work was presented at the 96th Annual Meeting of the American Association of Immunologists in 2009. Supported by the US National Institutes of Health (U19 AI83022 and U19 AI82630 to E.J.W.; and R01 AI66215 and R01 AI46719), the Department of Microbiology and Immunology (P.D.K.) and the Biotechnology and Biological Sciences Research Council and Medical Research Council (M.T.)
The authors declare no competing financial interests.
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Gracias, D., Stelekati, E., Hope, J. et al. The microRNA miR-155 controls CD8+ T cell responses by regulating interferon signaling. Nat Immunol 14, 593–602 (2013). https://doi.org/10.1038/ni.2576
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