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MicroRNA 31 inhibits CD8+ T-cell function by increasing its sensitivity to type I interferon signaling in chronic viral infection

Cellular & Molecular Immunology volume 15, pages 533–535 (2018)Cite this article

Chronic viral infections and malignant tumors can cause T cells to become dysfunctional and exhausted through two different associated immune statuses: inflammation and immunosuppression. Inflammatory immunity is a necessary step for the establishment of the immune response to control infection and cancer. However, once a pathogen cannot be cleared in time or a tumor continues to progress, an immunosuppressive environment involving various immune cells and cytokines may form, thereby promoting the persistence of the pathogen or tumor. Among those immune factors, type I interferons play a dual role by driving inflammation and inducing a variety of suppressive factors that limit immune responses in chronic infection and cancer.1 CD8+ T cells are the main effector cells that act against infection and tumors. Type I interferon signaling promotes the initial activation of CD8+ T cells, drives their cytolytic ability and is also critical for their survival. However, during chronic infection or tumor outgrowth, continued exposure to type I interferons impairs T-cell function and drives disease progression.

MiR-31 has been reported to be negatively correlated with the severity of systemic lupus erythematosus,4 suggesting that the molecule might have a role in weakening the immune response. Another study reported that miR-31 negatively regulates FOXP3 expression by binding directly to its potential target site in the 3′ UTR of FOXP3 mRNA.5 This appeared to be another aspect of miR-31’s role in the immune response, indicating that miR-31 may have the potential to enhance the immune response by disrupting the development of Treg cells. By comparing the profiling data of miRNAs in activated T cells, total thymocytes, B cells, T cells, bone marrow-derived DCs and LPS-treated DCs, Moffett et al.3 found that miR-31 may play a special role during T-cell activation and differentiation. The expression of miR-31 increased in T cells that have an effector/memory phenotype compared to their naive counterparts. Further investigation indicated that the induction of miR-31 is dependent on the calcium–NFAT pathway downstream of TCR signaling. Similar to this finding, Xue F et al.6 reported that miR-31 was upregulated during the activation of primary human T lymphocytes upon TCR stimulation. To investigate the genes or pathways targeted by miR-31, all mRNAs that were differentially expressed in CD8+ T cells transduced with lenti-miR-31 relative to their expression in CD8+ T cells transduced with lenti-eGFP were analyzed. The pathway analysis showed that several type I interferon pathway genes were significantly correlated with miR-31 expression. Furthermore, 13 targets were screened and validated. Among these genes, Ppp6c, Lats2, Oxsr1, Elavl1 and Stk40 have been reported as targets of miR-31, while eight mRNAs (Psd4, Sh2d1a, Ilf3, Coro7, Rab1b, Stra13, Cdkn1a and Ifi30) were newly identified targets of miR-31. To further investigate the impact of miR-31 on T-cell function, Moffett et al.3 compared the changes in the mRNA expression of T cells from wild-type mice and Mir31−/− mice after TCR activation with or without treatment of IFN-β. It was found that a number of effector molecules related to T-cell function were upregulated with miR-31 deficiency and became more pronounced after stimulation with IFN-β. This finding suggested that miR-31 attenuated the effect of the IFN-β signaling pathways on T cells. However, further studies showed that miR-31 deficiencies did not disrupt the expression of downstream molecules involved in IFN-β signaling, such as STAT1, STAT2 and IRF4. Additional experiments indicated that miR-31 might upregulate the sensitivity to type I interferons by targeting Ppp2c, which may inhibit type I interferon signaling through the kinase Map3k7.

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  1. Division of Research on Virology and Immunology, State Key Laboratory for Infectious Disease Prevention and Control, National Center for AIDS/STD Control and Prevention, China CDC, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Beijing, 102206, China

    Mingming Jia, Yiming Shao & Kunxue Hong

  2. Key Laboratory of Infection and Immunity, Institute of Biophysics, Chinese Academy of Sciences, 100101, Beijing, China

    Mingming Jia

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Correspondence to Kunxue Hong.

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Jia, M., Shao, Y. & Hong, K. MicroRNA 31 inhibits CD8+ T-cell function by increasing its sensitivity to type I interferon signaling in chronic viral infection. Cell Mol Immunol 15, 533–535 (2018). https://doi.org/10.1038/cmi.2017.99

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