The microRNA miR-155 controls CD8+ T cell responses by regulating interferon signaling

Abstract

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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Figure 1: Expression of miR-155 in CD8+ T cells.
Figure 2: CD8+ T cell responses require miR-155.
Figure 3: Overexpression of miR-155 augments CD8+ T cell responses.
Figure 4: Deficiency in miR-155 impairs the proliferation of CD8+ T cells and enhances the antiproliferative effect of IFN-β.
Figure 5: Molecular signature of activated miR-155-deficient CD8+ T cells shows enrichment for genes associated with type I interferon signaling.
Figure 6: Deficiency in miR-155 in CD8+ T cells leads to dysregulated expression of potential miR-155 target genes.
Figure 7: STAT1 expression is regulated by miR-155 and type I interferon signaling contributes to the proliferative defect of miR-155 deficiency.

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Acknowledgements

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.)

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D.T.G., infection with influenza virus, adoptive transfer, in vitro proliferation, immunoblot analysis, siRNA transfection, retroviral transduction and RT-PCR; E.S., infection with L. monocytogenes, adoptive transfer, in vitro proliferation, siRNA transfection and RT-PCR; J.L.H., A.C.B., J.A.F. and J.N., infection with influenza virus, flow cytometry, BrdU assays, RT-PCR and mouse breeding; T.A.D., E.S. and E.J.W., microarray data analysis; Y.M.M., adoptive transfer and data analysis; E.S., D.T.G., A.C.B., E.J.W., M.T. and P.D.K., study design, data analysis and manuscript authorship; and all authors, discussion of results and comments on the manuscript.

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Correspondence to Martin Turner or Peter D Katsikis.

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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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