Abstract
CD4+FOXP3+ regulatory T (Treg) cells are essential for maintaining immunological self-tolerance. Treg cell development and function depend on the transcription factor FOXP3, which is present in several distinct isoforms due to alternative splicing. Despite the importance of FOXP3 in the proper maintenance of Treg cells, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood. Here, we show that in human Treg cells IL-1β promotes excision of FOXP3 exon 7. FOXP3 is not only expressed by Treg cells but is also transiently expressed when naïve T cells differentiate into Th17 cells. Forced splicing of FOXP3 into FOXP3Δ2Δ7 strongly favored Th17 differentiation in vitro. We also found that patients with Crohn’s disease express increased levels of FOXP3 transcripts lacking exon 7, which correlate with disease severity and IL-17 production. Our results demonstrate that alternative splicing of FOXP3 modulates T cell differentiation. These results highlight the importance of characterizing FOXP3 expression on an isoform basis and suggest that immune responses may be manipulated by modulating the expression of FOXP3 isoforms, which has broad implications for the treatment of autoimmune diseases.
Highlights
The FOXP3 gene encodes a transcription factor that contains three functional domains including a proline-rich N-terminal domain encoded by exons 2–4, a zinc finger and leucine zipper domain encoded by exons 5–7, and a fork-head domain encoded by exons 9–119–12
The total amount of FOXP3 mRNA was calculated as the sum of FOXP3ex1/2 and FOXP3ex1/3 mRNA, which allowed us to determine the relative proportion of a specific splicing event
We demonstrate that patients suffering from Crohn’s disease display an irregular pattern of FOXP3 splicing with an increased proportion of FOXP3 transcripts lacking exon 7
Summary
The FOXP3 gene encodes a transcription factor that contains three functional domains including a proline-rich N-terminal domain encoded by exons 2–4, a zinc finger and leucine zipper domain encoded by exons 5–7, and a fork-head domain encoded by exons 9–119–12. The proline-rich N-terminal domain of FOXP3 enables the protein to interact with transcriptional repressors and activators, which alter gene expression and regulate the suppressive ability of Treg cells[13]. Alternative splicing allows a single gene to give rise to multiple proteins that can have different or even opposing functions. FOXP3 isoforms, full-length FOXP3 (FOXP3fl) and FOXP3 lacking exon 2 (FOXP3Δ 2), confer suppressive ability to Treg cells[17,18]. Despite the importance of FOXP3 in Treg cells, the regulation and functional consequences of FOXP3 isoform expression remains poorly understood
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