IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3
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IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3. / Mailer, Reiner K W; Joly, Anne-Laure; Liu, Sang; Elias, Szabolcs; Tegner, Jesper; Andersson, John.
In: SCI REP-UK, Vol. 5, 06.10.2015, p. 14674.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - IL-1β promotes Th17 differentiation by inducing alternative splicing of FOXP3
AU - Mailer, Reiner K W
AU - Joly, Anne-Laure
AU - Liu, Sang
AU - Elias, Szabolcs
AU - Tegner, Jesper
AU - Andersson, John
PY - 2015/10/6
Y1 - 2015/10/6
N2 - 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.
AB - 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.
KW - Alternative Splicing
KW - Blotting, Western
KW - Cell Differentiation
KW - Cells, Cultured
KW - Crohn Disease
KW - Forkhead Transcription Factors
KW - Humans
KW - Immune Tolerance
KW - Interleukin-17
KW - Interleukin-1beta
KW - Lymphocyte Activation
KW - Promoter Regions, Genetic
KW - Protein Isoforms
KW - RNA, Messenger
KW - Real-Time Polymerase Chain Reaction
KW - Reverse Transcriptase Polymerase Chain Reaction
KW - T-Lymphocytes, Regulatory
KW - Th17 Cells
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1038/srep14674
DO - 10.1038/srep14674
M3 - SCORING: Journal article
C2 - 26441347
VL - 5
SP - 14674
JO - SCI REP-UK
JF - SCI REP-UK
SN - 2045-2322
ER -
