Mini-reviewControl of T cell effector functions by miRNAs
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.
Section snippets
Th1 cell differentiation and function
Th1 cells are CD4+ T cells characterized by the production of IFN-γ, having an important role in the host defense against intracellular pathogens and tumours, although dysregulated Th1 responses can promote autoimmunity [21]. The differentiation of Th1 cells is initiated by the IFN-γ activation of signal transducer and activator of transcription (STAT)1 signaling, resulting in the expression of the TF T-bet, which in turn induces the production of IFNγ and runt-related transcription factor 3
Th2 cell activities
Th2 cells differentiation from activated CD4+ T cells is driven by IL-4, which signals through the TF STAT6, which in turn upregulates GATA3, collaborating with STAT5 to drive the production of key Th2 cell lineage-defining cytokines, IL-4, IL-5 and IL-13 [34]. By supporting basophil, mast cell, and eosinophil survival, Th2 cells promote protective immune responses, including control of parasitic infections, but also contribute to chronic inflammatory diseases, such as allergy and asthma [35].
Th17 cell differentiation and functions
Th17 cells are characterized by the production of IL-17 A, IL-17 F, IL-21, IL-22 and, in humans, IL-26, and play a key role in the host defence against opportunistic fungi or extracellular bacteria. On the other hand, Th17 cells play a pathogenic role in various inflammatory disorders, such as psoriasis, IBD and MS [21]. Th17 cell differentiation is initiated by IL-6 and transforming growth factor (TGF)-β, leading to RAR-related orphan receptor (ROR)γt expression, the former through STAT3
Treg cell function
Treg cells supress effector T cell responses, limiting inflammation and preventing autoimmunity. They are characterized by the expression of the TF Foxp3, and cell-surface maker CD25, and the immunosuppressive cytokines TGF-β and IL-10. Treg develop in the thymus and emigrate to the periphery where they are critical to prevent tissue autoimmunity, as highlighted by the phenotype of IPEX (immune deregulation polyendocrinopathy enteropathy X-linked) patients [2,56]. However, Treg can also
Tfh cell differentiation and functions
Follicular helper T (Tfh) cells have been recently identified as a subset of effector helper T cells, characterized by expression of CXCR5 (often co-expressed with PD-1) that are necessary for initiation and maintenance of the germinal center (GC) reaction, being thus crucial for the development of antigen-specific B cell immunity [13]. BCL6, a transcriptional repressor, promotes the differentiation of Tfh cells, whereas BLIMP-1 antagonizes BCL6 and enforces the differentiation into non-Tfh
CD8+ T cell differentiation and functions
CD8+ T cells are essential players of adaptive immunity, contributing to host defence against intracellular pathogens and tumours [14]. After antigen recognition, activated CD8+ T cells undergo proliferative expansion and differentiate into cytotoxic T lymphocytes (CTLs) that are able to produce effector molecules, including IFN-γ and cytotoxic molecules such as perforin and GZMB [75] and kill target cells.
Concomitant with major changes in transcriptome and genetic remodelling of signature
miRNA-mediated regulation of NKT cell function
NKT cells are thymus-derived, innate-like T lymphocytes that recognize glycolipid antigens presented by the CD1d, a non-classical MHC class Ib molecule [92]. Invariant NKT (iNKT) cells are the major subset of NKT cells and express TCRs composed by a restricted set of β chains and an invariant V14/Jα18 chain in mice or V24/Jα18 in humans [93,94]. iNKT cells serve an important role in early host defence against invading pathogens by rapidly secreting effector cytokines such as IL-4 and IFN-γ that
Physiological relevance of miRNAs regulating multiple effector T cell populations
As described in the previous sections, miRNAs play an essential role as regulators of effector T cell functions, either by regulating relevant TFs implicated in their development or differentiation or the effector cytokines themselves. In addition to miR-150 and miR-155, which play pleiotropic roles in immune cells, several miRNAs have been identified that affect simultaneously two or more effector T cell populations. These miRNAs might contribute to the plasticity and balance between different
Concluding remarks
miRNA-mediated regulation of T cell differentiation is essential to the homeostasis of the immune system. By targeting multiple critical genes, some miRNAs can individually regulate several cellular processes or signaling pathways, thus affecting the differentiation of various T cell subsets in different tissues. However, it is also a reality that several miRNAs are tissue/cell type specific, acting synergistically to produce a given phenotype, with expression patterns reflecting underlying
Conflicts of interest
The authors declared no competing interests.
Acknowledgments
We thank our past colleagues, Nina Schmolka and Paula Vargas Romero, for discussions on this topic. Our research was funded by Fundação para a Ciência e a Tecnologia (PTDC/BEX-BCM/3592/2014 to A.Q.G.); and European Research Council (CoG_646701 to B.S.-S.). This publication was also funded by LISBOA-01-0145-FEDER-007391, project cofunded by FEDER, through POR Lisboa 2020 - Programa Operacional Regional de Lisboa, PORTUGAL 2020, and Fundação para a Ciência e a Tecnologia.
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