Consequences of regulated pre-mRNA splicing in the immune system

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Abstract
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.