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  • Review Article
  • Published:

MicroRNAs as regulatory elements in immune system logic

A Corrigendum to this article was published on 23 May 2016

This article has been updated

Key Points

  • Several factors contribute to haematopoietic cell fate decisions, including transcription factors and microRNAs (miRNAs), which are a class of small non-coding RNAs that negatively regulate gene expression.

  • Several miRNAs have been found to participate in network motif architectures that influence haematopoietic cell fate decisions. These miRNAs may further serve to buffer target protein expression in response to environment stress or set protein expression thresholds at key developmental checkpoints.

  • Several miRNAs have recently been found to contribute to haematopoietic stem cell (HSC) survival and function. These miRNAs regulate diverse processes, including HSC reconstitution potential, self-renewal, differentiation, autophagy, apoptosis and response to inflammatory signals.

  • Innate immune cells, particularly macrophages and granulocytes, are perhaps the most well-studied system for miRNA regulation of immune development and function. However, little is known about the role of miRNAs in gene networks underlying megakaryocyte and erythroid cell development.

  • Several mechanisms have been uncovered by which miRNAs regulate adaptive immune cell development and function. These mechanisms include the regulation of key regulators of developmental checkpoints, fine-tuning of signalling pathways and modulation of the immune response.

  • Aberrant miRNA expression can have severe pathological consequences, including the development of autoimmune disease and cancer. Recent advances in gene-editing technology hold promise for modulating miRNA expression for therapeutic purposes.

Abstract

MicroRNAs (miRNAs) are crucial post-transcriptional regulators of haematopoietic cell fate decisions. They act by negatively regulating the expression of key immune development genes, thus contributing important logic elements to the regulatory circuitry. Deletion studies have made it increasingly apparent that they confer robustness to immune cell development, especially under conditions of environmental stress such as infectious challenge and ageing. Aberrant expression of certain miRNAs can lead to pathological consequences, such as autoimmunity and haematological cancers. In this Review, we discuss the mechanisms by which several miRNAs influence immune development and buffer normal haematopoietic output, first at the level of haematopoietic stem cells, then in innate and adaptive immune cells. We then discuss the pathological consequences of dysregulation of these miRNAs.

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Figure 1: Overview of immune system development and the regulatory elements governing HSC function.
Figure 2: The different roles of miRNAs in network motifs and in regulating gene expression.
Figure 3: Overview of miRNAs that alter HSC function.
Figure 4: miRNAs that regulate innate immune cell development and function.
Figure 5: miRNAs that regulate adaptive immune cell development and function.
Figure 6: miRNAs in aberrant haematopoiesis.

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Change history

  • 23 May 2016

    In the original version of this article, an incorrect arrowhead was used in Figure 2b, suggesting that factor Y negatively regulates microRNA X. This has now been corrected in the online version of the article to show that factor Y positively regulates microRNA X. Also, miR-146a was incorrectly listed as miR-46a in figure 5a, and this has now been corrected. The authors and Nature Reviews Immunology apologize for these errors.

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Acknowledgements

The preparation of this review was supported by the US National Institute of Health (RO1AI079243 to D.B.), the National Research Service Award (CA183220 to A.M.) and the University of California, Los Angeles/California Institute of Technology Medical Scientist Training Program (A.M.). The authors also thank J. Zhao, D. Rao and M. Mann for their comments in preparation of this manuscript.

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Correspondence to Arnav Mehta or David Baltimore.

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Glossary

Haematopoiesis

The physiological process of creating immune cells in our body.

Long-term haematopoietic stem cell

(LT-HSC). A cell from which all other immune cells originate and that has the unique ability to self-renew.

Multipotent progenitors

(MPPs). Early haematopoietic progenitors that can differentiate into all mature immune cell types but do not have the ability to self-renew.

Autophagy

A normal physiological process through which the cell degrades unnecessary cellular components.

3′ untranslated region

(3′ UTR). The sequence of an mRNA that is downstream of the stop codon.

Robustness

The resilience of different cellular functions to perturbations from extracellular insults.

Protein expression noise

The intrinsic variation in translation that results in different protein expression levels with the same mRNA input.

Bistable switch

A network motif in which there is a binary outcome of either expression of one gene or another.

Microprocessor complex

The complex of two enzymes, Drosha and DGCR8, that cleave pri-miRNAs to pre-mRNAs.

Buffering protein expression

Maintaining the expression of a protein to within a narrowly defined range.

Master regulator

A regulatory element that is essential for the regulation of a developmental process.

Competing endogenous RNAs

(ceRNA). RNAs that bind microRNAs and prevent them from interacting with functionally relevant mRNA targets.

Polycistron

A collection of microRNAs that are expressed in a single transcriptional unit.

miRNA sponge

(microRNA sponge). A transcript with several miRNA-binding sites that is used to downregulate the functional response of a miRNA.

Exhaustion

A state of cellular dysfunction or loss that occurs after aberrant activation and proliferation of a cell.

Rheostat

A gene that allows, through its cellular function, for graded, quantitative control of a biological process, such as cell signalling.

B1 B cells

A subset of B cells expressing high levels of IgM that secrete low-affinity, broad specificity antibodies.

Germinal centre

Sites within lymph nodes, the spleen and other secondary lymphoid organs where mature B cells proliferate and undergo class-switch recombination and somatic hypermutation.

Class-switch recombination

(CSR). The somatic recombination process by which the class of an immunoglobulin is switched from IgM to IgA, IgE or IgG.

B2 B cells

Conventional B cells that secrete highly specific high-affinity antibodies.

Activation-induced deaminase

(AID). An RNA-editing enzyme that is essential for class-switch recombination and somatic hypermutation.

Somatic hypermutation

(SHM). The somatic process by which the antibody repertoire of an activated B cell is mutated to achieve much higher specificity, which is then required for B cell proliferation and survival in the germinal centre.

Double negative 1

(DN1). An early developmental stage of T cell progenitors in the thymus that do not express either CD4 or CD8.

Double positive

(DP). A late developmental stage of T cell progenitors in the thymus that express both CD4 and CD8 on their surface.

Oncomirs

MicroRNAs that lead to cancerous transformation when overexpressed.

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Mehta, A., Baltimore, D. MicroRNAs as regulatory elements in immune system logic. Nat Rev Immunol 16, 279–294 (2016). https://doi.org/10.1038/nri.2016.40

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