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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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Abstract

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.

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Acknowledgements

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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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). https://doi.org/10.1038/ni.2073

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