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.
At a glance
Gene Expression Omnibus
- Micromanagement of the immune system by microRNAs. Nat. Rev. Immunol. 8, 120–130 (2008). , , &
- Conserved seed pairing, often flanked by adenosines, indicates that thousands of human genes are microRNA targets. Cell 120, 15–20 (2005). , &
- A pattern-based method for the identification of microRNA binding sites and their corresponding heteroduplexes. Cell 126, 1203–1217 (2006). et al.
- Most mammalian mRNAs are conserved targets of microRNAs. Genome Res. 19, 92–105 (2009). , , &
- MicroRNA maturation: stepwise processing and subcellular localization. EMBO J. 21, 4663–4670 (2002). , , , &
- Argonaute2 is the catalytic engine of mammalian RNAi. Science 305, 1437–1441 (2004). et al.
- Nuclear export of microRNA precursors. Science 303, 95–98 (2004). , , , &
- Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005). et al.
- Dicer controls CD8+ T-cell activation, migration, and survival. Proc. Natl. Acad. Sci. USA 107, 21629–21634 (2010). &
- Multiple proto-oncogene activations in avian leukosis virus-induced lymphomas: evidence for stage-specific events. Mol. Cell Biol. 9, 2657–2664 (1989). &
- Requirement of bic/microRNA-155 for normal immune function. Science 316, 608–611 (2007). et al.
- microRNA-155 regulates the generation of immunoglobulin class-switched plasma cells. Immunity 27, 847–859 (2007). et al.
- Regulation of the germinal center response by microRNA-155. Science 316, 604–608 (2007). et al.
- Pre-B cell proliferation and lymphoblastic leukemia/high-grade lymphoma in E(mu)-miR155 transgenic mice. Proc. Natl. Acad. Sci. USA 103, 7024–7029 (2006). et al.
- Modulation of miR-155 and miR-125b levels following lipopolysaccharide/TNF-α stimulation and their possible roles in regulating the response to endotoxin shock. J. Immunol. 179, 5082–5089 (2007). et al.
- MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010). et al.
- Cutting edge: The Foxp3 target miR-155 contributes to the development of regulatory T cells. J. Immunol. 182, 2578–2582 (2009). et al.
- Foxp3-dependent microRNA155 confers competitive fitness to regulatory T cells by targeting SOCS1 protein. Immunity 30, 80–91 (2009). et al.
- MicroRNA miR-155 affects antiviral effector and effector memory CD8 T cell differentiation. J. Virol. 87, 2348–2351 (2013). , , &
- Micro-RNA 155 Is required for optimal CD8+ T cell responses to acute viral and intracellular bacterial challenges. J. Immunol. 190, 1210–1216 (2013). , &
- Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J. Exp. Med. 202, 637–650 (2005). , , , &
- IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J. Immunol. 174, 4465–4469 (2005). et al.
- Modulation of STAT1 protein levels: a mechanism shaping CD8 T-cell responses in vivo. Blood 107, 987–993 (2006). , , &
- Virus-induced transient immune suppression and the inhibition of T cell proliferation by type I interferon. J. Virol. 85, 5929–5939 (2011). , &
- Attrition of bystander CD8 T cells during virus-induced T-cell and interferon responses. J. Virol. 75, 5965–5976 (2001). et al.
- An endogenous positively selecting peptide enhances mature T cell responses and becomes an autoantigen in the absence of microRNA miR-181a. Nat. Immunol. 10, 1162–1169 (2009). , , , &
- miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007). et al.
- miR-155 regulates IFN-γ production in natural killer cells. Blood 119, 3478–3485 (2012). et al.
- Gene regulation and chromatin remodeling by IL-12 and type I IFN in programming for CD8 T cell effector function and memory. J. Immunol. 183, 1695–1704 (2009). et al.
- Microarray analysis of primary endothelial cells challenged with different inflammatory and immune cytokines. Cytokine 29, 256–269 (2005). , , , &
- HO-1 upregulation suppresses type 1 IFN pathway in hepatic ischemia/reperfusion injury. Transplant. Proc. 37, 1677–1678 (2005). , , , &
- Downstream of tyrosine kinases-1 and Src homology 2-containing inositol 5′-phosphatase are required for regulation of CD4+CD25+ T cell development. J. Immunol. 176, 3958–3965 (2006). et al.
- Inositol phosphatase SHIP1 is a primary target of miR-155. Proc. Natl. Acad. Sci. USA 106, 7113–7118 (2009). , , &
- Smad signaling antagonizes STAT5-mediated gene transcription and mammary epithelial cell differentiation. J. Biol. Chem. 283, 1293–1307 (2008). et al.
- Interferon-α inhibits Stat5 DNA-binding in IL-2 stimulated primary T-lymphocytes. Eur. J. Biochem. 269, 29–37 (2002). et al.
- T cell activation induces a noncoding RNA transcript sensitive to inhibition by immunosuppressant drugs and encoded by the proto-oncogene, BIC. Cell Immunol. 217, 78–86 (2002). et al.
- Down-modulation of responses to type I IFN upon T cell activation. J. Immunol. 170, 749–756 (2003). , , , &
- Interferon-α inhibits proliferation in human T lymphocytes by abrogation of interleukin 2-induced changes in cell cycle-regulatory proteins. Cell Growth Differ. 10, 575–582 (1999). et al.
- Stat1 and Stat2 but not Stat3 arbitrate contradictory growth signals elicited by α/β interferon in T lymphocytes. Mol. Cell Biol. 25, 5456–5465 (2005). , , &
- Cutting edge: role of STAT1, STAT3, and STAT5 in IFN-αβ responses in T lymphocytes. J. Immunol. 174, 609–613 (2005). et al.
- Transcripts targeted by the microRNA-16 family cooperatively regulate cell cycle progression. Mol. Cell Biol. 27, 2240–2252 (2007). et al.
- MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. Mol. Cell 26, 753–767 (2007). , &
- Lineage relationship and protective immunity of memory CD8 T cell subsets. Nat. Immunol. 4, 225–234 (2003). et al.
- Immunological control of murine gammaherpesvirus infection is independent of perforin. J. Gen. Virol. 78, 2025–2030 (1997). et al.
- Memory CD8+ T cells require CD28 costimulation. J. Immunol. 179, 6494–6503 (2007). et al.
- Dendritic cells and CD28 costimulation are required to sustain virus-specific CD8+ T cell responses during the effector phase in vivo. J. Immunol. 186, 4599–4608 (2011). et al.
- Silencing of SOCS1 enhances antigen presentation by dendritic cells and antigen-specific anti-tumor immunity. Nat. Biotechnol. 22, 1546–1553 (2004). , , &
- The role of Bach1 in the induction of heme oxygenase by tin mesoporphyrin. Biochem. Biophys. Res. Commun. 354, 757–763 (2007). , , &
- Loss of SOCS3 gene expression converts STAT3 function from anti-apoptotic to pro-apoptotic. J. Biol. Chem. 281, 36683–36690 (2006). et al.
- Multiple regulatory domains control IRF-7 activity in response to virus infection. J. Biol. Chem. 275, 34320–34327 (2000). , &
- Summaries of Affymetrix GeneChip probe level data. Nucleic Acids Res. 31, e15 (2003). et al.
- Significance analysis of microarrays applied to the ionizing radiation response. Proc. Natl. Acad. Sci. USA 98, 5116–5121 (2001). , &
- GenePattern 2.0. Nat. Genet. 38, 500–501 (2006). et al.
- Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl. Acad. Sci. USA 102, 15545–15550 (2005). et al.
- Supplementary Text and Figures (599 KB)
Supplementary Figures 1–3 and Supplementary Table 1