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  • Review Article
  • Published:

Micromanagement of the immune system by microRNAs

Nature Reviews Immunology volume 8, pages 120–130 (2008)Cite this article

A Corrigendum to this article was published on 15 February 2008

Key Points

  • MicroRNA (miRNA) genes encode long primary RNA transcripts that are processed into a precursor miRNA (pre-miRNA) that is ∼60 nucleotides in length. The pre-miRNA is then further processed to provide the mature miRNA.

  • Mature miRNAs are ∼22-nucleotide small non-coding RNAs that are thought to regulate gene expression at the post-transcriptional level by targeting mRNA for degradation or translational repression.

  • Systematic cloning and computational predictions indicate that there are hundreds of miRNA genes in animals; humans may have as many as one thousand miRNA genes.

  • Some primary miRNAs are synthesized by RNA polymerase II and have 5′ caps and 3′ poly(A) tails, whereas others might be transcribed by RNA polymerase III.

  • Some of the protein machinery that processes primary transcripts into pre-miRNAs and mature miRNAs is also used in the RNA interference (RNAi) pathways and is functionally important for animal development.

  • The expression of miRNAs is temporally and spatially regulated during animal development. Some miRNAs are differentially expressed during haematopoietic lineage differentiation.

  • Computational analyses have shown that miRNAs may regulate over one-third of the protein-coding genes in the human genome.

  • miRNAs have important roles in regulating the development and function of immune cells.

  • Altered miRNA levels are associated with various cancers, including leukaemias and lymphomas.

  • Mice deficient for miR-155 are immunodeficient, and have defects in the function of B cells, T cells and dendritic cells, as well as in the development of T helper cells and germinal centres.

  • miR-181a could function as an antigen sensitivity rheostat to modulate T-cell sensitivity to antigens during T-cell development and maturation by downregulating the expression of multiple phosphatases in the T-cell receptor signalling pathway.

  • Viral genomes encode miRNAs that are used to regulate viral and host gene expression and modulate the function of host immune cells.

  • Host miRNAs may be used to target viral genome to either repress or potentiate viral replication.

Abstract

MicroRNAs (miRNAs) are an abundant class of evolutionarily conserved small non-coding RNAs that are thought to control gene expression by targeting mRNAs for degradation or translational repression. Emerging evidence suggests that miRNA-mediated gene regulation represents a fundamental layer of genetic programmes at the post-transcriptional level and has diverse functional roles in animals. Here, we provide an overview of the mechanisms by which miRNAs regulate gene expression, with specific focus on the role of miRNAs in regulating the development of immune cells and in modulating innate and adaptive immune responses.

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Figure 1: MicroRNAs (miRNAs) and miRNA genes.
Figure 2: MicroRNA biogenesis and function in animal cells.
Figure 3: Modulation of the antigen sensitivity of T cells by the miR-181a dimmer switch (or rheostat).
Figure 4: MicroRNAs in host–pathogen interaction.

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Acknowledgements

We thank members of the Chen and Lodish laboratories and also V. Ambros for his helpful comments on this manuscript. This research on miRNAs is supported by grants 1R01HL081612-01 to C.-Z. C. and 5R01DK068348 to H.F.L.

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Authors and Affiliations

  1. Whitehead Institute for Biomedical Research and Department of Biology, Massachusetts Institute of Technology, Nine Cambridge Center, Cambridge, 02142, Massachusetts, USA

    Harvey F. Lodish & Beiyan Zhou

  2. Department of Microbiology and Immunology, Baxter Laboratory of Genetic Pharmacology, Stanford University School of Medicine, 269 Campus Drive, Stanford, CCSR 3205, 94305-5175, California, USA

    Gwen Liu & Chang-Zheng Chen

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  1. Harvey F. Lodish
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  2. Beiyan Zhou
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  3. Gwen Liu
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Correspondence to Harvey F. Lodish or Chang-Zheng Chen.

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FURTHER INFORMATION

miRBase targets

miRNA registry

PicTar

TargetScan

Glossary

Forward genetics

A classical genetic analysis approach that proceeds from phenotype to genotype by positional cloning or candidate-gene analysis.

RNA-induced silencing complex

(RISC). A multi-protein small interfering RNA (siRNA) complex that binds short antisense RNA strands and guides the cleavage of target RNAs. This complex is thought to be important for post-transcriptional gene regulation by siRNAs and microRNAs.

Microarray analysis

A technique for measuring the transcription of genes. It involves hybridization of fluorescently labelled cDNA prepared from a cell or tissue of interest with glass slides or other surfaces dotted with thousands of oligonucleotides or cDNA, ideally representing all expressed genes in the species.

Polysome profile

Polysomes (or polyribosomes) are a cluster of ribosomes that are attached along the length of a single molecule of mRNA. Polysomes read this mRNA simultaneously, helping to synthesize the same protein at different spots on the mRNA. A polysome profile refers to the distribution of polysomes as determined by gradient centrifugation of cytoplasmic extracts. The method is used to study the association of mRNAs with ribosomes.

m7G cap

The 7-methylguanosine that is linked by a triphosphate bridge to the first transcribed nucleotide at the 5′ end of eukaryotic mRNA. Recognition of the m7G cap by the cap-binding protein eIF4E is the initiation step of cap-dependent translation.

Argonaute (AGO) proteins

A large family of ∼95 KDa proteins that contain conserved PAZ (piwi, argonaut and zwille) and PIWI domains and are involved in post-transcriptional gene silencing. Mammals have four AGO family members (AGO1, AGO2, AGO3 and AGO4), each of which might be a component of an RNA-induced silencing complex.

Seed nucleotides

This term refers to the seven nucleotides found at the 5′ region of an miRNA (nucleotides 2–8). Many computational target prediciton programmes require an exact Watson–Crick complementary match between the target sites and the seed nucleotides of a mature miRNA.

Small interfering RNAs

(siRNAs). A class of double-stranded RNAs (dsRNAs) of ∼21 nucleotides in length, generated from long dsRNAs. siRNAs silence gene expression by promoting the cleavage of perfectly matched mRNAs. siRNAs can also be generated by in vitro synthesis and can be used to 'knockdown' (that is, to silence the expression of) a specific gene.

Chromatin immunoprecipitation

(ChIP). The use of antibodies specific for transcription factors to precipitate nucleic-acid sequences from chromatin for amplification.

B-1 cells

IgMhiIgDlowMac1+B220lowCD23- cells that are dominant in the peritoneal and pleural cavities. Their precursors develop in the fetal liver and omentum, and in adult mice, the size of the B-1-cell population is kept constant owing to the self-renewing capacity of these cells. B-1 cells recognize self components, as well as common bacterial antigens, and they secrete antibodies that tend to have low affinity and broad specificity.

RNA interference

A mechanism for RNA-guided regulation of gene silencing in which double-stranded RNA inhibits the expression of genes with complementary nucleotide sequences.

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Lodish, H., Zhou, B., Liu, G. et al. Micromanagement of the immune system by microRNAs. Nat Rev Immunol 8, 120–130 (2008). https://doi.org/10.1038/nri2252

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