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IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3.

Mailer RK, Joly AL, Liu S, Elias S, Tegner J, Andersson J - Sci Rep (2015)

Bottom Line: 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.Our results demonstrate that alternative splicing of FOXP3 modulates T cell differentiation.

View Article: PubMed Central - PubMed

Affiliation: Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

Alternative splicing of FOXP3 exon 7 correlates with IL-17A expression.Quantitative PCR was used to measure FOXP3 and IL-17A transcript levels in colon biopsies from patients suffering from Crohn’s disease and normalized to GAPDH expression (n = 26). Data are presented as mean of n = 3 technical replicates. P < 0.05 was considered significant, Spearman rank correlation test; r = correlation coefficient).
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f4: Alternative splicing of FOXP3 exon 7 correlates with IL-17A expression.Quantitative PCR was used to measure FOXP3 and IL-17A transcript levels in colon biopsies from patients suffering from Crohn’s disease and normalized to GAPDH expression (n = 26). Data are presented as mean of n = 3 technical replicates. P < 0.05 was considered significant, Spearman rank correlation test; r = correlation coefficient).

Mentions: Based on research with murine cells indicating that exon 2 of Foxp3 binds to and antagonizes ROR-γt2223, it has been suggested that FOXP3Δ2 may be linked to increased levels of IL-17 production in humans. However, a recent study with patients suffering from inflammatory bowel disease could not verify such an association24. Here, we analyzed biopsies obtained from Crohn’s disease patients and determined the levels of FOXP3 mRNA splice variants and cytokine mRNA expression. In accordance with previous studies we found no correlation between FOXP3ex1/3 and IL-17A expression. However, we observed a significant positive correlation between the levels of FOXP3ex6/8 mRNA and IL-17A mRNA (Fig. 4). Furthermore, no correlations were evident between FOXP3 splice variants and IFN-γ (data not shown), suggesting that alternative splicing of FOXP3 specifically affects Th17 differentiation. Altogether, these results suggest that FOXP3Δ2Δ7 favors the differentiation of naïve T cells towards Th17 cells in the setting of Crohn’s disease.


IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3.

Mailer RK, Joly AL, Liu S, Elias S, Tegner J, Andersson J - Sci Rep (2015)

Alternative splicing of FOXP3 exon 7 correlates with IL-17A expression.Quantitative PCR was used to measure FOXP3 and IL-17A transcript levels in colon biopsies from patients suffering from Crohn’s disease and normalized to GAPDH expression (n = 26). Data are presented as mean of n = 3 technical replicates. P < 0.05 was considered significant, Spearman rank correlation test; r = correlation coefficient).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4593960&req=5

f4: Alternative splicing of FOXP3 exon 7 correlates with IL-17A expression.Quantitative PCR was used to measure FOXP3 and IL-17A transcript levels in colon biopsies from patients suffering from Crohn’s disease and normalized to GAPDH expression (n = 26). Data are presented as mean of n = 3 technical replicates. P < 0.05 was considered significant, Spearman rank correlation test; r = correlation coefficient).
Mentions: Based on research with murine cells indicating that exon 2 of Foxp3 binds to and antagonizes ROR-γt2223, it has been suggested that FOXP3Δ2 may be linked to increased levels of IL-17 production in humans. However, a recent study with patients suffering from inflammatory bowel disease could not verify such an association24. Here, we analyzed biopsies obtained from Crohn’s disease patients and determined the levels of FOXP3 mRNA splice variants and cytokine mRNA expression. In accordance with previous studies we found no correlation between FOXP3ex1/3 and IL-17A expression. However, we observed a significant positive correlation between the levels of FOXP3ex6/8 mRNA and IL-17A mRNA (Fig. 4). Furthermore, no correlations were evident between FOXP3 splice variants and IFN-γ (data not shown), suggesting that alternative splicing of FOXP3 specifically affects Th17 differentiation. Altogether, these results suggest that FOXP3Δ2Δ7 favors the differentiation of naïve T cells towards Th17 cells in the setting of Crohn’s disease.

Bottom Line: 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.Our results demonstrate that alternative splicing of FOXP3 modulates T cell differentiation.

View Article: PubMed Central - PubMed

Affiliation: Translational Immunology Unit, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus