MicroRNA-mediated regulation of T helper cell differentiation and plasticity

Abstract

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.

Figure 1. miRNA regulation of T helper cell activation

a | MicroRNAs are important regulators of effector T cell differentiation, including T cell activation, acquisition of effector functions such as cytokine production, and T cell proliferation (top panel). Genetic ablation of key molecules of the miRNA biogenesis pathway in CD4⁺ T cells underlines the importance of miRNAs for these processes (lower panel). Activation of microRNA-deficient CD4⁺ T cells results in increased and aberrant cytokine production, reduced cell proliferation. b | Mechanistic overview illustrating miRNA participation in regulatory networks that control T cell activation, expansion, and effector cell differentiation. Note that specific miRNAs are both regulated targets and upstream regulators of signaling pathways that govern T cell behavior. Selected miRNA target genes are indicated. T_EFF, effector T cell; T_naive, naïve T cell.

Figure 2. miRNA regulation of IFNγ production

IFN-γ production and signaling in Th1 cells is regulated by several miRNAs at distinct levels. The lineage determining transcription factor T-bet induces expression of the Th1 hallmark cytokine IFN-γ. T-bet is induced by TCR signaling, by IL-12 via STAT4 signaling, and by IFN-γ itself in a positive feedback loop via STAT1. miR-146a directly targets STAT1 and the NFκB signaling molecules TRAF6 and IRAK1. TCR activation induces miR-155, which in turn downregulates negative regulators of cytokine signaling SHIP1 and SOCS1. However, miR-155 has also been proposed to induce downregulation of IFNγR1. miR-29 limits Th1 cell differentiation and IFN-γ production by targeting the mRNAs encoding T-bet, Eomes, and IFN-γ itself.

Figure 3. miRNA regulation of T_Reg function and plasticity

a | Treg-specific miRNA expression is required to restrain effector T cell responses. In the absence of miRNA expression in T_Reg cells, for example due to deletion of essential components of the miRNA biogenesis pathway, such as DICER or DROSHA, T_Reg cells fail to maintain tolerance, which might result in autoimmunity. b | Examples of miRNA pathways that contribute to the regulation of T_Reg cell function and plasticity. T_EFF, effector T cell; T_Reg, regulatory T cell.