Role of RNA Alternative Splicing in T Cell Function and Disease

Figures

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  Figure 1. Alternative splicing of Fas exon 6 in activated T cells. (A) Fas exon 6 is alternatively spliced to produce two transcript isoforms: the exon 6—included isoform encoding for membrane-bound Fas receptor and the exon 6—skipped isoform encoding for soluble Fas protein. Activated T cells express higher levels of the membrane-bound Fas receptor, which is required for apoptotic signaling in these cells, and thus inhibit uncontrolled T cell proliferation. (B) The presence of an SNP in the 3′SS of intron 5 (indicated in red) in the Fas gene results in an increased skipping of exon 6 and skews the isoform ratios of Fas in activated T cells. Increased levels of soluble Fas isoform results in increased and unregulated T cell proliferation.

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  Figure 2. Antisense modulation of IL7R splicing controls sIL7R expression. Expression of the membrane-bound (mIL7R) and soluble (sIL7R) isoforms of IL7R is determined by alternative splicing of IL7R exon 6, and this splicing event is influenced by the MS risk SNP rs6897932 (C*/T, where C* is the risk allele). The risk C* allele of rs6897932 enhances the exclusion of exon 6 and the levels of sIL7R, leading to the development of autoimmunity. The expression of sIL7R can be controlled for therapeutic intervention by modulating the splicing of exon 6 with antisense oligonucleotides (ASOs): ABS-066 promotes the inclusion of exon 6 and reduces sIL7R for the treatment of autoimmunity, whereas ABS-001 promotes the exclusion of exon 6 and enhances sIL7R to enhance antitumor immunity.