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  • Review Article
  • Published:

MicroRNA-mediated regulation of T helper cell differentiation and plasticity

Nature Reviews Immunology volume 13, pages 666–678 (2013)Cite this article

Subjects

Key Points

  • T helper (TH) cells are a central component of the adaptive immune system. They coordinate cellular and humoral responses by producing cytokines and growth factors. Several TH cell subsets have been described, including TH1, TH2, TH9, TH17 and TH22 cells, regulatory T (TReg) cells and T follicular helper (TFH) cells.

  • MicroRNAs are small evolutionarily conserved nucleotide sequences that regulate gene expression by interfering with mRNA translation and stability.

  • MicroRNA-deficient CD4+ T cells show impaired survival and proliferation, but also have an increased sensitivity to signals that induce effector TH cell differentiation and cytokine production.

  • An increasing number of individual microRNAs and co-expressed microRNA clusters have been shown to have marked effects on TH cell fate decisions and immune functions.

  • MicroRNAs are crucial for the proper regulation of TReg cell development, homeostasis and plasticity, and for the maintenance of immune tolerance.

  • Research on microRNA function can be used as a tool for the discovery of novel pathways that regulate TH cell biology and might identify novel targets for the treatment of conditions in which TH cell functions are impaired or exaggerated.

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.

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Figure 1: miRNA-mediated regulation of T helper cell activation.
Figure 2: miRNA-mediated regulation of IFNγ production.
Figure 3: miRNA-mediated regulation of TReg cell function and plasticity.

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Acknowledgements

This work was supported by the US National Institutes of Health (grants HL109102 and HL107202), by a Scholar Award from the Leukemia & Lymphoma Society (to K.M.A.) and by the Swiss Foundation for Grants in Biology and Medicine (D.B.).

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

    Dirk Baumjohann & K. Mark Ansel

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  1. Dirk Baumjohann
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Correspondence to K. Mark Ansel.

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FURTHER INFORMATION

miRBase

TargetScan

miRTarBase

PowerPoint slides

Glossary

T helper cells

(TH cells). Effector T cells that develop from naive CD4+ T cells. Following their activation, TH cells produce cytokines that regulate cellular and humoral immunity.

miRNA-induced silencing complex

(miRISC). The microRNA-induced silencing complex consists of a microRNA (miRNA) bound to an Argonaute protein. The miRNA provides sequence specificity for the function of the complex in translational repression and in decreasing target mRNA stability.

miRNomes

All of the microRNAs expressed in cells or organisms.

Positive selection

The process by which immature T cells are selected in the thymus for the expression of a functional T cell receptor.

Negative selection

The process by which immature T cells that have a high affinity for self antigens are deleted in the thymus to prevent the egress of autoreactive T cells into the circulation.

miRNA family

MicroRNAs (miRNAs) are classified into families that share the same seed sequence and are therefore predicted to share many of the same target mRNAs; for example, the polycistronic miR-17∼92 cluster comprises six miRNAs representing four separate miRNA families — the miR-17 family (miR-17 and miR-20a), the miR-18 family (miR-18a), the miR-19 family (miR-19a and miR-19b) and the miR-25 family (miR-92a).

miRNA clusters

MicroRNAs (miRNAs) are often found in clusters in the genome and these clusters are typically transcribed together to form primary miRNA transcripts that are processed to yield multiple mature miRNAs.

Seed recognition sequences

Sequences on mRNA targets that are recognized by the seed sequence of a microRNA; that is, by the nucleotides in positions 2–8 of the microRNA 5′ end.

miRNA sponge

A genetically engineered construct containing several microRNA-binding sites that compete with endogenous microRNA-binding sites; this decreases specific microRNA availability and function.

miRNA mimics

Small transfectable synthetic RNAs that mimic endogenous microRNAs; they are used to study the effects of microRNA overexpression.

Antagomir

A small synthetic nucleic acid oligonucleotide that binds to endogenous microRNAs (miRNAs) and inhibits their function. Antagomirs are often chemically modified to promote their stability and/or their entry into target cells. Also known as anti-miR, miRNA inhibitor or miRNA antagonist.

Locked nucleic acid

(LNA). An RNA oligonucleotide bearing a modification of the ribose moiety in its backbone that 'locks' it in a favourable conformation for base pairing, which increases its binding affinity. LNAs are used in various applications for microRNA detection and in microRNA inhibitors for experimental and therapeutic use.

Experimental autoimmune encephalomyelitis

(EAE). An animal model of multiple sclerosis, which is a chronic demyelinating disease in humans. In animals, EAE can be induced by the injection of several different antigens that are derived from the myelin sheath, including myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein, together with a potent adjuvant.

Germinal centres

Specialized anatomical structures in secondary lymphoid organs in which T follicular helper cells provide help to B cells to generate high-affinity antibodies, memory B cells and long-lived plasma cells.

Secondary lymphoid organs

Organized lymphoid structures in which adaptive immune responses are induced; for example, the spleen and the lymph nodes.

Processing bodies

(P-bodies). Molecular structures in the cytoplasm that are major sites of mRNA turnover.

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Baumjohann, D., Ansel, K. MicroRNA-mediated regulation of T helper cell differentiation and plasticity. Nat Rev Immunol 13, 666–678 (2013). https://doi.org/10.1038/nri3494

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