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The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ

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Interferon-γ (IFN-γ) has a critical role in immune responses to intracellular bacterial infection. MicroRNAs (miRNAs) are important in the regulation of innate and adaptive immunity. However, whether miRNAs can directly target IFN-γ and regulate IFN-γ production post-transcriptionally remains unknown. Here we show that infection of mice with Listeria monocytogenes or Mycobacterium bovis bacillus Calmette-Guérin (BCG) downregulated miR-29 expression in IFN-γ-producing natural killer cells, CD4+ T cells and CD8+ T cells. Moreover, miR-29 suppressed IFN-γ production by directly targeting IFN-γ mRNA. We developed mice with transgenic expression of a 'sponge' target to compete with endogenous miR-29 targets (GS29 mice). We found higher serum concentrations of IFN-γ and lower L. monocytogenes burdens in L. monocytogenes–infected GS29 mice than in their littermates. GS29 mice had enhanced T helper type 1 (TH1) responses and greater resistance to infection with BCG or Mycobacterium tuberculosis. Therefore, miR-29 suppresses immune responses to intracellular pathogens by targeting IFN-γ.

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Figure 1: Infection with an intracellular pathogen upregulates IFN-γ production but downregulates miR-29 expression in activated NK cells and T cells.
Figure 2: NF-κB mediates the transcriptional suppression of miR-29 in activated, IFN-γ-producing NK cells and T cells.
Figure 3: Direct targeting of the 3′ UTR of IFN-γ mRNA by miR-29.
Figure 4: Downregulation of IFN-γ production in activated primary CD4+ and CD8+ T cells by miR-29.
Figure 5: Generation of GS29 mice and verification of the involvement of miR-29 in regulating IFN-γ production in vivo.
Figure 6: Greater resistances of GS29 mice to L. monocytogenes infection.
Figure 7: More potent TH1 responses and delayed-type hypersensitivity in GS29 mice infected with BCG.

Change history

  • 04 April 2014

    In the version of this supplementary file originally posted online, the curves for the isotype-matched control antibodies in the plots for CD44 and CD62L in Supplementary Figure 7 were incorrect. The error has been corrected in this file as of 4 April 2014.


  1. 1

    He, L. & Hannon, G.J. MicroRNAs: small RNAs with a big role in gene regulation. Nat. Rev. Genet. 5, 522–531 (2004).

    CAS  Article  Google Scholar 

  2. 2

    Baltimore, D., Boldin, M.P., O'Connell, R.M., Rao, D.S. & Taganov, K.D. MicroRNAs: new regulators of immune cell development and function. Nat. Immunol. 9, 839–845 (2008).

    CAS  Article  Google Scholar 

  3. 3

    O'Connell, R.M., Rao, D.S., Chaudhuri, A.A. & Baltimore, D. Physiological and pathological roles for microRNAs in the immune system. Nat. Rev. Immunol. 10, 111–122 (2010).

    CAS  Article  Google Scholar 

  4. 4

    Monticelli, S. et al. MicroRNA profiling of the murine hematopoietic system. Genome Biol. 6, R71 (2005).

    Article  Google Scholar 

  5. 5

    Wu, H. et al. miRNA profiling of naive, effector and memory CD8 T cells. PLoS ONE 2, e1020 (2007).

    Article  Google Scholar 

  6. 6

    Sandberg, R., Neilson, J.R., Sarma, A., Sharp, P.A. & Burge, C.B. Proliferating cells express mRNAs with shortened 3′ untranslated regions and fewer microRNA target sites. Science 320, 1643–1647 (2008).

    CAS  Article  Google Scholar 

  7. 7

    Li, Q.J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007).

    CAS  Article  Google Scholar 

  8. 8

    Ebert, P.J., Jiang, S., Xie, J., Li, Q.J. & Davis, M.M. 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).

    CAS  Article  Google Scholar 

  9. 9

    Stittrich, A.B. et al. The microRNA miR-182 is induced by IL-2 and promotes clonal expansion of activated helper T lymphocytes. Nat. Immunol. 11, 1057–1062 (2010).

    CAS  Article  Google Scholar 

  10. 10

    Lu, L.F. et al. Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142, 914–929 (2010).

    CAS  Article  Google Scholar 

  11. 11

    Du, C. et al. MicroRNA miR-326 regulates TH-17 differentiation and is associated with the pathogenesis of multiple sclerosis. Nat. Immunol. 10, 1252–1259 (2009).

    CAS  Article  Google Scholar 

  12. 12

    O'Connell, R.M. et al. MicroRNA-155 promotes autoimmune inflammation by enhancing inflammatory T cell development. Immunity 33, 607–619 (2010).

    CAS  Article  Google Scholar 

  13. 13

    Taganov, K.D., Boldin, M.P., Chang, K.J. & Baltimore, D. NF-κB-dependent induction of microRNA miR-146, an inhibitor targeted to signaling proteins of innate immune responses. Proc. Natl. Acad. Sci. USA 103, 12481–12486 (2006).

    CAS  Article  Google Scholar 

  14. 14

    O'Connell, R.M., Taganov, K.D., Boldin, M.P., Cheng, G. & Baltimore, D. MicroRNA-155 is induced during the macrophage inflammatory response. Proc. Natl. Acad. Sci. USA 104, 1604–1609 (2007).

    CAS  Article  Google Scholar 

  15. 15

    Bezman, N.A. et al. Distinct requirements of microRNAs in NK cell activation, survival, and function. J. Immunol. 185, 3835–3846 (2010).

    CAS  Article  Google Scholar 

  16. 16

    Schoenborn, J.R. & Wilson, C.B. Regulation of interferon-γ during innate and adaptive immune responses. Adv. Immunol. 96, 41–101 (2007).

    CAS  Article  Google Scholar 

  17. 17

    Pamer, E.G. Immune responses to Listeria monocytogenes. Nat. Rev. Immunol. 4, 812–823 (2004).

    CAS  Article  Google Scholar 

  18. 18

    North, R.J. & Jung, Y.J. Immunity to tuberculosis. Annu. Rev. Immunol. 22, 599–623 (2004).

    CAS  Article  Google Scholar 

  19. 19

    Redford, P.S. et al. Enhanced protection to Mycobacterium tuberculosis infection in IL-10-deficient mice is accompanied by early and enhanced Th1 responses in the lung. Eur. J. Immunol. 40, 2200–2210 (2010).

    CAS  Article  Google Scholar 

  20. 20

    Young, H.A. & Bream, J.H. IFN-γ: recent advances in understanding regulation of expression, biological functions, and clinical applications. Curr. Top. Microbiol. Immunol. 316, 97–117 (2007).

    CAS  PubMed  Google Scholar 

  21. 21

    Muljo, S.A. et al. Aberrant T cell differentiation in the absence of Dicer. J. Exp. Med. 202, 261–269 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Chong, M.M., Rasmussen, J.P., Rudensky, A.Y. & Littman, D.R. The RNAseIII enzyme Drosha is critical in T cells for preventing lethal inflammatory disease. J. Exp. Med. 205, 2005–2017 (2008).

    CAS  Article  Google Scholar 

  23. 23

    Dai, R. et al. Suppression of LPS-induced Interferon-gamma and nitric oxide in splenic lymphocytes by select estrogen-regulated microRNAs: a novel mechanism of immune modulation. Blood 112, 4591–4597 (2008).

    CAS  Article  Google Scholar 

  24. 24

    Hou, J. et al. MicroRNA-146a feedback inhibits RIG-I-dependent Type I IFN production in macrophages by targeting TRAF6, IRAK1, and IRAK2. J. Immunol. 183, 2150–2158 (2009).

    CAS  Article  Google Scholar 

  25. 25

    Wang, P. et al. Inducible microRNA-155 feedback promotes type I IFN signaling in antiviral innate immunity by targeting suppressor of cytokine signaling 1. J. Immunol. 185, 6226–6233 (2010).

    CAS  Article  Google Scholar 

  26. 26

    Barrett, T. et al. NCBI GEO: mining millions of expression profiles–database and tools. Nucleic Acids Res. 33, D562–D566 (2005).

    CAS  Article  Google Scholar 

  27. 27

    Betel, D., Wilson, M., Gabow, A., Marks, D.S. & Sander, C. The resource: targets and expression. Nucleic Acids Res. 36, D149–D153 (2008).

    CAS  Article  Google Scholar 

  28. 28

    Wang, H. et al. NF-kappaB-YY1-miR-29 regulatory circuitry in skeletal myogenesis and rhabdomyosarcoma. Cancer Cell 14, 369–381 (2008).

    CAS  Article  Google Scholar 

  29. 29

    Park, S.Y., Lee, J.H., Ha, M., Nam, J.W. & Kim, V.N. miR-29 miRNAs activate p53 by targeting p85α and CDC42. Nat. Struct. Mol. Biol. 16, 23–29 (2009).

    CAS  Article  Google Scholar 

  30. 30

    Xiong, Y. et al. Effects of microRNA-29 on apoptosis, tumorigenicity, and prognosis of hepatocellular carcinoma. Hepatology 51, 836–845 (2010).

    CAS  PubMed  Google Scholar 

  31. 31

    Nathans, R. et al. Cellular microRNA and P bodies modulate host-HIV-1 interactions. Mol. Cell 34, 696–709 (2009).

    CAS  Article  Google Scholar 

  32. 32

    Landgraf, P. et al. A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129, 1401–1414 (2007).

    CAS  Article  Google Scholar 

  33. 33

    Mott, J.L. et al. Transcriptional suppression of mir-29b-1/mir-29a promoter by c-Myc, hedgehog, and NF-κB. J. Cell. Biochem. 110, 1155–1164 (2010).

    CAS  Article  Google Scholar 

  34. 34

    Szabo, S.J. et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 100, 655–669 (2000).

    CAS  Article  Google Scholar 

  35. 35

    Gebeshuber, C.A., Zatloukal, K. & Martinez, J. miR-29a suppresses tristetraprolin, which is a regulator of epithelial polarity and metastasis. EMBO Rep. 10, 400–405 (2009).

    CAS  Article  Google Scholar 

  36. 36

    Serbina, N.V., Jia, T., Hohl, T.M. & Pamer, E.G. Monocyte-mediated defense against microbial pathogens. Annu. Rev. Immunol. 26, 421–452 (2008).

    CAS  Article  Google Scholar 

  37. 37

    Franco-Zorrilla, J.M. et al. Target mimicry provides a new mechanism for regulation of microRNA activity. Nat. Genet. 39, 1033–1037 (2007).

    CAS  Article  Google Scholar 

  38. 38

    Ebert, M.S., Neilson, J.R. & Sharp, P.A. MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells. Nat. Methods 4, 721–726 (2007).

    CAS  Article  Google Scholar 

  39. 39

    Gentner, B. et al. Stable knockdown of microRNA in vivo by lentiviral vectors. Nat. Methods 6, 63–66 (2009).

    CAS  Article  Google Scholar 

  40. 40

    Loya, C.M., Lu, C.S., Van Vactor, D. & Fulga, T.A. Transgenic microRNA inhibition with spatiotemporal specificity in intact organisms. Nat. Methods 6, 897–903 (2009).

    CAS  Article  Google Scholar 

  41. 41

    Dorhoi, A. et al. The adaptor molecule CARD9 is essential for tuberculosis control. J. Exp. Med. 207, 777–792 (2010).

    CAS  Article  Google Scholar 

  42. 42

    Mogues, T., Goodrich, M.E., Ryan, L., LaCourse, R. & North, R.J. The relative importance of T cell subsets in immunity and immunopathology of airborne Mycobacterium tuberculosis infection in mice. J. Exp. Med. 193, 271–280 (2001).

    CAS  Article  Google Scholar 

  43. 43

    Bafica, A. et al. TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis. J. Exp. Med. 202, 1715–1724 (2005).

    CAS  Article  Google Scholar 

  44. 44

    Wang, C. et al. The E3 ubiquitin ligase Nrdp1 'preferentially' promotes TLR-mediated production of type I interferon. Nat. Immunol. 10, 744–752 (2009).

    CAS  Article  Google Scholar 

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We thank T. Chen, J. Hou and C. Han for discussions; Y. Li and M. Jin for technical support; C. Ni for pathological analysis; and H. Shen (University of Pennsylvania School of medicine) for L. monocytogenes. Supported by the National Key Basic Research Program of China (2007CB512403 and 2009CB521902), the National Natural Science Foundation of China (30721091, 30731160623), the Shanghai Committee of Science and Technology (10dz1910300) and the National High Biotechnology Development Program of China (2009ZX09503-003, 2009ZX09503-023).

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X.C. and F.M. designed the experiments; F.M., S.X., X.L., Q.Z., X.X., M.L., M.H., N.L. and H.Y. did the experiments; and X.C., F.M. and S.X. wrote the manuscript.

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Correspondence to Xuetao Cao.

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The authors declare no competing financial interests.

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Ma, F., Xu, S., Liu, X. et al. The microRNA miR-29 controls innate and adaptive immune responses to intracellular bacterial infection by targeting interferon-γ. Nat Immunol 12, 861–869 (2011).

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