Cancer Letters

Cancer Letters

Volume 423, 1 June 2018, Pages 147-152
Cancer Letters

Mini-review
Diverse functions of miR-17–92 cluster microRNAs in T helper cells

https://doi.org/10.1016/j.canlet.2018.02.035Get rights and content

Highlights

  • MicroRNAs (miRNAs) are critical molecular regulators of T helper cells.

  • The miR-17–92 cluster is induced in activated CD4+ T cells.

  • miR-17–92 regulates T helper cell proliferation, differentiation, and function.

  • miR-17–92 consists of six miRNAs that represent four different miRNA families.

  • Individual miRNAs of this cluster can have cooperative or opposing effects on target gene networks.

Abstract

T helper (Th) cells are critically involved in adaptive immune responses against various pathogens. In contrast, dysregulated T helper cell responses are associated with a variety of diseases, including autoimmunity, allergies, and cancer. Differentiation of naïve CD4+ T cells into effector T helper cell subsets, including Th1, Th2, Th17, Treg, and T follicular helper (Tfh), requires precise dosing of signaling molecules and transcription factors. MicroRNAs (miRNAs), which are small endogenously expressed RNAs that regulate gene expression, play important roles in these processes. The miR-17–92 cluster, a miRNA polycistron also known as oncomiR-1, has emerged as a central integrator of gene expression events that govern T helper cell differentiation pathways. The complexity of miR-17–92-mediated gene regulation lies in the nature of this miRNA cluster, which consists of six different miRNAs. Individual miR-17–92 miRNAs, albeit initially transcribed as one transcript, can have cooperative or opposing effects on biological processes. Therefore, a better understanding of the molecular regulation of miR-17–92 and its downstream networks will provide important insights into T helper cell differentiation and diversity that may be harnessed for the design of advanced T cell-targeting therapies.

Introduction

Since the original discovery of two distinct T helper (Th) cell populations, termed Th1 and Th2, several other T helper cell subsets have been described to better accommodate for the many different functions of T helper cells [1,2]. While initially the separation of T helper cells into two major categories was based on functional characteristics, e.g. cytokine production associated with help for intracellular bacterial clearance versus help to B cells, T helper cells can also be subdivided according to their expression patterns of chemokine receptors that determine their migration and homing behaviors or according to their use of ‘lineage-defining’ transcription factors. Over the last few years, it has become clear that T helper cells are more flexible and plastic in their gene expression and cell identity than previously anticipated and that small variations in gene expression can govern cell fate decisions made by these cells [[3], [4], [5]]. Accordingly, T helper cells might not represent stable lineages or subsets, but more adequately represent a continuum of various cellular qualities that are subject to dynamic changes. MicroRNAs (miRNAs), which are small endogenously expressed RNAs that regulate gene expression, have been shown to be important regulators of proper T helper cell differentiation and function [[6], [7], [8], [9]]. This is in line with early studies in which global miRNA expression was disrupted specifically in T cells [[10], [11], [12]]. Since then, the contribution of individual miRNAs and miRNA clusters has been investigated in more detail. Naïve CD4+ T cells express high amounts of miRNAs that are believed to stabilize the naïve T cell state by repressing genes that are involved in activation and differentiation [13]. Upon stimulation, the majority of the miRNA pool is downregulated, while only a few miRNAs are upregulated [14]. Despite their intrinsic inhibitory nature, these few miRNAs act in concert with transcription factors as drivers of cell differentiation processes that ultimately shape T helper cell fate decisions and identity [15].

Section snippets

The complex nature of the miR-17–92 cluster

The polycistronic miR-17–92 cluster, which is referred to as an ‘oncomir’ due to its transforming potential, exhibits various functions in health and disease and represents one of the best-studied miRNA clusters [[16], [17], [18]]. The miR-17–92 cluster consists of six individual miRNAs that are transcribed as a single transcript, including miR-17, miR-18a, miR-19a, miR-19b, miR-20a, and miR-92a. In addition to miR-17–92, two additional paralogous clusters exist, miR-106a–363 and miR-106b–25.

Th1 cells

Th1 cells orchestrate cellular immune responses against viral and bacterial infections and are also involved in the pathogenesis of several autoimmune diseases. Th1 cells express the transcription factor T-bet and the chemokine receptor CXCR3, and they produce large amounts of IFNγ. First evidence that Th1 cells are regulated by miRNAs came from a study in which global miRNA-deficiency, caused by deletion of Dicer in CD4+ T cells, resulted in preferential production of IFNγ in vitro, even under

Conclusion and future directions

Over the last decade, the availability of various genetic tools, including conditional alleles that allow transgenic overexpression [29] or deletion [51] of miR-17–92, has fueled research on the role of miR-17–92 in regulating different aspects of T helper cell biology (Table 1). It has become clear that T helper cell subsets share many common miR-17–92-regulated processes, but that there are also several differences in the contribution of this cluster to differentiation and function of the

Conflicts of interest

The author declares that there are no conflicts of interest.

Acknowledgements

The author would like to thank Vigo Heissmeyer and Julia Maul for discussions and critical reading of the manuscript. This work was supported by the Deutsche Forschungsgemeinschaft (Emmy Noether Programme BA 5132/1-1 and SFB 1054 Teilprojekt B12).

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