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  • Review Article
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Consequences of regulated pre-mRNA splicing in the immune system

Nature Reviews Immunology volume 4, pages 931–940 (2004)Cite this article

Key Points

  • Alternative splicing of a pre-mRNA enables the production of multiple functionally distinct proteins from a single gene. This mechanism of gene regulation is widespread, with particular prevalence in the immune system.

  • Sequences in exons and introns can influence the pattern of splicing of a given gene. Therefore, translationally silent mutations can alter protein expression by changing the splicing of a pre-mRNA, with potential disease consequences.

  • The protein tyrosine kinases FYN, SYK and possibly LCK, are differentially spliced in T cells. At least two isoforms are predicted for each protein, with one isoform being more efficient at promoting T-cell signalling.

  • Cytokine signalling in T cells might also be influenced by alternative splicing. Functionally distinct isoforms have been detected for the cytokines interleukin-2 (IL-2), IL-4 and IL-6, the receptors for IL-4 and IL-7 and the cytokine-induced signalling molecules protein tyrosine kinase 2 (PYK2), myeloid differentiation primary-response gene 88 (MyD88) and IL-1 receptor-associated kinase 1 (IRAK1).

  • The expression of cell-surface molecules, such as CD44, intercellular adhesion molecule 1 (ICAM1), platelet/endothelial cell-adhesion molecule 1 (PECAM1), CD45 and cytotoxic T-lymphocyte antigen 4 (CTLA4) is also influenced by alternative splicing to generate either soluble forms of the molecules or molecules with altered protein–protein interactions. Splicing-dependent changes in the expression of these molecules have been shown to influence the threshold of T-cell activation.

  • Regulation of splicing in response to antigen stimulation has been observed or implied for CD44, CD45, FYN, CTLA4, PECAM1 and MyD88. The mechanisms by which activation-induced splicing regulation occurs are beginning to be understood for the CD44 and CD45 genes, and recent data indicate that some of these alternative splicing events might be regulated by overlapping pathways.

Abstract

Alternative splicing is widely recognized to be a ubiquitous and crucial mechanism for generating protein diversity and regulating protein expression. Numerous immunologically relevant genes have been found to undergo alternative splicing; however, there has been little effort to develop a coherent picture of how alternative splicing might be used as a general mechanism to regulate the function of the immune system. In this review, I summarize the mechanisms by which splicing is controlled in T cells, and discuss the role of alternative splicing and alternative isoform expression in the regulation of T-cell activation and function.

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Figure 1: Basic patterns of alternative splicing.
Figure 2: Alternative splicing of CD44 and CD45 pre-mRNA.
Figure 3: Proposed models for the regulation of CD44 and CD45 alternative splicing.

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Acknowledgements

I thank B. Graveley, K. Hertel, C. Wuelfing and members of laboratory for critical comments on the manuscript.

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  1. Department of Biochemistry, The University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines boulevard, Dallas, 75390-9038, Texas, USA

    Kristen W. Lynch

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DATABASES

Entrez

CD44

CD45

CTLA4

FYN

ICAM1

IL-2

IL-4

IL-6

IL-4Rα

IL-6Rα

IL-6Rβ

IL-7Rα

IRAK1

IRAK4

LCK

LFA1

MyD88

p72

PECAM1

PYK2

SAM68

SYK

TLR4

YB1

Glossary

SPLICING

The processing of pre-mRNA such that introns are removed and exons are joined directly to one another.

CASSETTE EXONS

Exons that are included in only a percentage of the final mRNA transcripts that are derived from a given pre-mRNA.

MUTUALLY EXCLUSIVE EXONS

Two or more exons in a single pre-mRNA that are never both included in the final mRNA transcript.

SPLICE SITES

Conserved sequences at the exon–intron boundaries that direct the splicing machinery and determine the precise location of pre-mRNA cleavage and exon joining.

SPLICEOSOME

A ribonucleoprotein complex that is involved in splicing of nuclear pre-mRNA. It is composed of five small nuclear ribonucleoproteins (snRNPs) and more than 50 non-snRNPs that recognize and assemble on exon–intron boundaries to catalyse intron processing of the pre-mRNA.

SR PROTEIN

A group of highly conserved, serine (S)- and arginine (R)-rich splicing-regulatory proteins. In most experimental systems, binding of an SR protein to an exon leads to exon inclusion.

HETEROGENEOUS NUCLEAR RIBONUCLEOPARTICLE PROTEIN

(HnRNP protein). A class of diverse RNA-binding proteins that associate with nascent pre-mRNA and can influence splicing. Several experimental systems have shown that binding of an hnRNP protein to an exon leads to exon skipping.

EXONIC SPLICING SILENCERS

(ESSs). Sequences in an exon that promote exon skipping.

EXONIC SPLICING ENHANCERS

(ESEs). Sequences in an exon that promote exon recognition and inclusion.

INTRONIC SPLICING SILENCERS

(ISSs). Sequences in an intron that promote skipping of a flanking exon.

INTRONIC SPLICING ENHANCERS

(ISEs). Sequences in an intron that promote recognition and inclusion of a flanking exon.

IMMUNOLOGICAL SYNAPSE

A stable region of contact between a T cell and an antigen-presenting cell that forms through cell–cell interaction of adhesion molecules. The mature immunological synapse contains two distinct, membrane domains: a central cluster of T-cell receptors, known as the central supramolecular activation cluster (cSMAC) and a surrounding ring of adhesion molecules known as the peripheral SMAC.

FOUR-HELICAL BUNDLE

A structural motif in proteins in which four α-helices are packed together.

DOMINANT-NEGATIVE INHIBITOR

A protein variant that inhibits the proper function of the co-expressed wild-type protein.

MIXED LEUKOCYTE REACTION

A tissue-culture technique for testing T-cell reactivity. The proliferation of one population of T cells, induced by exposure to inactivated MHC-mismatched stimulator cells, is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.

EXON SKIPPING

Exclusion of an exon from a pre-mRNA into the final mature mRNA transcript.

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Lynch, K. Consequences of regulated pre-mRNA splicing in the immune system. Nat Rev Immunol 4, 931–940 (2004). https://doi.org/10.1038/nri1497

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