Control of T cell effector functions by miRNAs

Highlights

• miRNAs as key post-transcriptional regulators of effector T cell differentiation.

• miRNAs that act as regulators of CD4 T cell- (Th1, Th2, Th7, Tfh and Treg cells), CD8⁺ T cell- and NKT cell- differentiation.

• Physiological relevance of miRNAs that affect simultaneously two or more effector T cell populations.

Abstract

The differentiation of effector T cells is a tightly regulated process that relies on the selective expression of lineage-defining master regulators that orchestrate unique transcriptional programs, including the production of distinct sets of effector cytokines. miRNAs are post-transcriptional regulators that are now viewed as critical players in these gene expression networks and help defining cell identity and function. This review summarises the role of individual miRNAs in the regulation of the differentiation of effector T cell subsets, including CD4⁺ T helper cells, cytotoxic CD8⁺ T cells and innate-like NKT cells. Moreover, we refer to miRNAs that have been identified to affect simultaneously two or more effector T cell populations, impacting on the balance between effector T cells in vivo, thus constituting potential biomarkers or targets for therapies aiming at boosting immunity or controlling autoimmunity.

Introduction

T lymphocytes develop in the thymus to acquire a T cell receptor (TCR) that undergoes key selection processes to attest productive somatic rearrangement (positive selection) while avoiding self-reactivity (negative selection). For most T cells, this is the result of molecular interactions between the TCR and peptide-major histocompatibility complex (MHC) complexes, although for a minor subset of Natural Killer (NK)-like, NKT cells, the selecting element is CD1d presenting glycolipids [1]. For conventional T cells, the outcome of the preferential TCR binding to MHC class I or II is the selection into the CD8⁺ or CD4⁺ T cell lineages, respectively. CD8⁺ T cells leave the thymus to become cytotoxic T lymphocytes (CTLs) upon cognate antigen recognition in the periphery. Most CD4⁺ T cells retain a naïve phenotype in the thymus, and will only differentiate into T helper (Th) cells upon activation in secondary lymphoid organs; however, 5–10% of CD4⁺ thymocytes undergo commitment to the regulatory T cell lineage, characterized by the expression of the master transcription factor (TF) Foxp3.

The peripheral differentiation of T cells relies on the selective expression of other lineage-defining master regulators that orchestrate unique transcriptional programs allowing the different T cell populations to secrete distinct sets of effector cytokines and other effector molecules [2]. In addition to transcriptional regulation, the establishment and maintenance of each effector T cell subset also involve the expression of epigenetic regulators such as microRNAs (miRNAs) that either promote or inhibit its differentiation and/or function. There has been growing evidence that miRNAs are an integral part of gene expression networks, determining cell identity and function by posttranscriptional repression of target mRNAs, including Th polarization, CD8⁺ T cell functions and NKT cell differentiation [[3], [4], [5], [6]].

miRNAs are small (∼22 nucleotides) noncoding RNAs which in mammals are transcribed by RNA polymerase II and processed by RNase III proteins Drosha and Dicer, interacting with an Argonaut (AGO) protein to form an effector complex called miRNA-induced silencing complex (miRISC) [7] miRISC is then guided by the miRNA to induce translational repression, deadenylation or decay of a target mRNA recognized by base pairing of the miRNA 5′ end “seed” domain (nucleotides 2 to 7) to usually the 3′ untranslated region (UTR) of the mRNA target [7]. miRNA-deficient T cells generated by specific genetic inactivation of either Drosha, DGCR8 (an essential cofactor of Drosha) or Dicer exhibit reduced proliferation and survival after in vitro stimulation, as well as an increase in effector Th cell differentiation and cytokine production, namely interferon-γ (IFN-γ) production, implying that miRNAs regulate T cell differentiation and might have an effect in the balance between different T cell populations, including, for example, Th1/Th17 versus regulatory T cells (Treg), or Th1 vs Th2 differentiation [[8], [9], [10]]. Ultimately, the balance between distinct T cell subsets impacts on the regulation of inflammation and autoimmunity. For example, whereas IFN-γ-producing Th1 and interleukin (IL)-17-producing Th17 are pro-inflammatory T cells that can be beneficial in a context of infection but detrimental in chronic inflammation and autoimmune disease [11], the anti-inflammatory functions of Treg cells have a protective role in chronic inflammation and autoimmunity [12]. Other T cell subsets, such as follicular helper T cells (Tfh) cells, are critical determinants of antigen-specific B cell immunity [13], whereas CD8⁺ T cells provide cellular immunity against intracellular pathogens and tumours [14]. It is thus of major importance to understand the miRNA-based mechanisms of gene regulation that underlie the differentiation, maintenance and functional plasticity of T cells, which may contribute to the development of novel diagnostic tools and immune therapies.

Several miRNAs, such as miR-181a and miR-214 have been implicated, respectively, in regulating thymic selection by T cells and in promoting T cell activation paying a general role in T cell function overall and acting upstream of T cell differentiation [[15], [16], [17], [18]]. Here we provide an updated [6,19,20], extended and integrated review on the multifaceted impact of miRNAs on T cell differentiation, including Th1, Th2, Th17, Treg, Tfh, CD8⁺ and NKT cells, and the balance between different effector or regulatory cell subtypes, thus highlighting the potential of using miRNA-based strategies to boost immunity or control autoimmunity.