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-1À promotes excision of FOXP3 exon 7. FOXP3 is not only expressed by Treg cells but is also transiently expressed when naive T cells differentiate into Th17 cells. Forced splicing of FOXP3 into FOXP3 ¢2¢7 strongly favored Th17 differentiation in vitro. We also found that patients with Crohnfs 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.
|Original language||English (US)|
|State||Published - Oct 6 2015|
Bibliographical noteFunding Information:
We thank Ludvig Linton and the staff at the Gastroenterology Clinic at Danderyd’s hospital for help with patient samples. This work was supported by the Swedish Research Council (projects: 2008–3055 and 2012-1851), the Swedish Cancer Foundation, the Swedish Heart-Lung Foundation, the Swedish Society of Medicine and Sigurd and Elsa Goljes minne.
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