Alternative Splicing of FOXP3-Virtue and Vice

Abstract

FOXP3 is the lineage-defining transcription factor of CD4+ CD25+ regulatory T cells. While many aspects of its regulation, interaction, and function are conserved among species, alternatively spliced FOXP3 isoforms are expressed only in human cells. This review summarizes current knowledge about alternative splicing of FOXP3 and the specific functions of FOXP3 isoforms in health and disease. Future perspectives in research and the therapeutic potential of manipulating alternative splicing of FOXP3 are discussed.

Keywords: FOXP3; FOXP3Δ2; FOXP3Δ2Δ7; Th17 cells; Treg cells; alternative splicing; antisense oligonucleotides; isoform.

Figure 1

Overview of genetic, transcriptional, and functional features of human FOXP3. (A) Structure of the FOXP3 pre-mRNA. Codons interrupted by introns are represented by convex and concave shapes for 1 and 2 nucleotides overhang, respectively. Alternative splicing of exon 2 and exon 7 is displayed by red lines; asterisks mark immunodysregulation, polyendocrinopathy, enteropathy, X-linked mutations that target alternatively spliced exons (black) or introns predicted to affect alternative splicing (red) and carcinoma mutations in alternatively spliced exons (blue). (B) FOXP3 protein with alternatively spliced exons (red), numbers indicate the region or the first amino acid of a new exon; dashed lines indicate regions of functional domains. (C) Cofactors binding FOXP3 functional domains, color-coded as in (B) numbers indicate the binding region, isoform-specific interactions highlighted in red.

Figure 2

Overview of FOXP3 isoform functions. T cell antigen receptor (TCR) signaling promotes the generation of the full-length FOXP3 isoform FOXP3fl. Nuclear export signals (NES) in FOXP3fl enable recruitment of cytoplasmic cofactors [e.g., phosphorylated signal transducer and activator of transcription 3 (pSTAT3) and histone acetyltransferase-1 (HAT1)]. In the nucleus, exon 2 and exon 7 of FOXP3fl bind to retinoid acid receptor-related orphan receptors (ROR) and forkhead box P1 (FOXP1), respectively. FOXP3fl induces Treg cell development, T cell anergy, and suppression. FOXP3Δ2 lacks a NES in exon 2 and supports Treg cell-mediated suppression but fails to interact with pSTAT3 and ROR; both FOXP3fl and FOXP3Δ2 inhibit Th17 cell differentiation. IL-1β signaling induces the generation of FOXP3Δ2Δ7 that lacks NES in exon 2 and exon 7. FOXP3Δ2Δ7 promotes Th17 cell differentiation and acts as dominant-negative inhibitor of FOXP3fl and FOXP3Δ2.