MicroRNA-mediated regulation of T helper cell differentiation and plasticity

Journal name:
Nature Reviews Immunology
Year published:
Published online


CD4+ T helper (TH) cells regulate appropriate cellular and humoral immune responses to a wide range of pathogens and are central to the success of vaccines. However, their dysregulation can cause allergies and autoimmune diseases. The CD4+ T cell population is characterized not only by a range of distinct cell subsets, such as TH1, TH2 and TH17 cells, regulatory T cells and T follicular helper cells — each with specific functions and gene expression programmes — but also by plasticity between the different TH cell subsets. In this Review, we discuss recent advances and emerging ideas about how microRNAs — small endogenously expressed oligonucleotides that modulate gene expression — are involved in the regulatory networks that determine TH cell fate decisions and that regulate their effector functions.

At a glance


  1. miRNA-mediated regulation of T helper cell activation.
    Figure 1: miRNA-mediated regulation of T helper cell activation.

    a | MicroRNAs (miRNAs) are important regulators of effector T cell differentiation, including T cell activation, proliferation and the acquisition of effector functions such as cytokine production (left panel). The genetic ablation of key molecules of the miRNA biogenesis pathway in CD4+ T cells highlighted the importance of miRNAs in these processes. The activation of miRNA-deficient CD4+ T cells results in increased and aberrant cytokine production and decreased cell proliferation (right panel). b | A mechanistic overview of the participation of miRNAs in regulatory networks that control T cell activation, the expansion of the T cell population and effector T cell differentiation is shown. The T cell receptor (TCR) signalling cascade activates nuclear factor of activated T cells (NFAT) and nuclear factor-κB (NF-κB), both of which induce the upregulation of miR-155 expression. miR-155 targets SH2 domain-containing inositol polyphosphate 5′ phosphatase 1 (Ship1) and suppressor of cytokine signalling 1 (Socs1), and promotes T cell activation and population expansion. NF-κB signalling also induces the expression of miR-146a, which inhibits T cell activation and population expansion through a negative feedback loop involving the miR-146a target genes TNF receptor-associated factor 6 (Traf6) and interleukin-1 receptor-associated kinase 1 (Irak1). Mammalian target of rapamycin (mTOR) signalling results in accelerated miRNA turnover and promotes T cell survival and proliferation partly through MYC-induced miR-17~92 expression. The high levels of expression of miR-125b in human naive CD4+ T cells impede T cell differentiation by repressing T cell effector genes, including interferon-γ (IFNG), IL2RB and PRDM1 (the gene encoding B lymphocyte-induced maturation protein 1 (BLIMP1)). The downregulation of inhibitory phosphatases such as dual-specificity protein phosphatase 5 (Dusp5), Dusp6, protein tyrosine phosphatase non-receptor type 22 (Ptpn22) and SH2 domain-containing protein tyrosine phosphatase 2 (Shp2) by miR-181a increases TCR signalling. IL-2-induced miR-182 expression interferes with T cell population expansion by targeting the transcription factor forkhead box protein O1 (Foxo1). It is worth noting that specific miRNAs are both regulated targets and upstream regulators of signalling pathways that control T cell behaviour. AGO2, Argonaute 2; Bim, BCL-2-interacting mediator of cell death; DC, dendritic cell; Pten, phosphatase and tensin homologue.

  2. miRNA-mediated regulation of IFN[gamma] production.
    Figure 2: miRNA-mediated regulation of IFNγ production.

    Interferon-γ (IFNγ) production and signalling in T helper 1 (TH1) cells is regulated by several microRNAs (miRNAs) at distinct levels. The lineage-determining T-box transcription factor T-bet induces expression of the TH1 cell hallmark cytokine IFNγ. T-bet is induced by T cell receptor (TCR) signalling, by interleukin-12 receptor (IL-12R) signalling via signal transducer and activator of transcription 4 (STAT4), and by IFNγ receptor (IFNGR) signalling in a positive feedback loop via STAT1. miR-146a directly targets Stat1 and the nuclear factor-κΒ (NF-κB) signalling molecules TNF receptor-associated factor 6 (Traf6) and IL-1R-associated kinase 1 (Irak1). TCR activation induces the expression of miR-155, which in turn downregulates the negative regulators of cytokine signalling SH2 domain-containing inositol polyphosphate 5′ phosphatase 1 (Ship1) and suppressor of cytokine signalling 1 (Socs1). However, miR-155 has also been proposed to induce the downregulation of Ifngr1. miR-29 limits TH1 cell differentiation and IFNγ production by targeting the mRNAs encoding T-bet, eomesodermin (Eomes) and IFNγ itself. DC, dendritic cell.

  3. miRNA-mediated regulation of TReg cell function and plasticity.
    Figure 3: miRNA-mediated regulation of TReg cell function and plasticity.

    a | The regulatory T (TReg) cell-specific expression of microRNAs (miRNAs) is required to restrain effector T cell responses. In the absence of miRNA expression in TReg cells — for example, because of a deficiency of Dicer or Drosha — TReg cells fail to maintain tolerance, which results in autoimmunity. b | Examples of the miRNA-mediated pathways that contribute to the regulation of TReg cell function and plasticity are shown. miR-146a expression in TReg cells prevents interferon-γ (IFNγ)-mediated T helper 1 (TH1) cell pathology through the inhibition of its direct target signal transducer and activator of transcription 1 (Stat1). miR-155 promotes TReg cell maintenance by inhibiting suppressor of cytokine signalling 1 (Socs1), which is a negative regulator of interleukin-2 receptor (IL-2R) signalling. Retinoic acid-induced miR-10a expression suppresses the conversion of TReg cells into T follicular helper (TFH) cells under certain conditions by the inhibition of TFH cell-associated transcriptional repressor B cell lymphoma-6 (Bcl6) and the nuclear co-repressor 2 (Ncor2). Although the miR-17~92 cluster has been shown to restrain different aspects of TReg cell biology, the precise mechanisms by which miR-17~92 regulates these processes remain largely unknown.


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  1. Department of Microbiology and Immunology, Sandler Asthma Basic Research Center, University of California, San Francisco, California 94143, USA.

    • Dirk Baumjohann &
    • K. Mark Ansel

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The authors declare no competing interests.

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  • Dirk Baumjohann

    Dirk Baumjohann is currently a postdoctoral fellow in the laboratory of K. Mark Ansel at the University of California, San Francisco, California, USA. He received his Ph.D. in cell biology and immunology from the University of Bern, Switzerland, for work with Federica Sallusto at the Institute for Research in Biomedicine in Bellinzona, Switzerland. His recent studies focus on understanding how microRNAs and transcription factors regulate T helper cell differentiation.

  • K. Mark Ansel

    K. Mark Ansel is Assistant Professor of microbiology & immunology in the Sandler Asthma Basic Research Center at the University of California, San Francisco (UCSF), California, USA. He completed his Ph.D. in biomedical sciences in Jason Cyster's laboratory at UCSF, and conducted postdoctoral research with Anjana Rao at Harvard Medical School, Cambridge, Massachusetts, USA. His laboratory studies microRNA-mediated regulation in the immune system. K. Mark Ansel's homepage.

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