ICER is requisite for Th17 differentiation

Nobuya Yoshida; Denis Comte; Masayuki Mizui; Kotaro Otomo; Florencia Rosetti; Tanya N. Mayadas; José C. Crispín; Sean J. Bradley; Tomohiro Koga; Michihito Kono; Maria P. Karampetsou; Vasileios C. Kyttaris; Klaus Tenbrock; George C. Tsokos

doi:10.1038/ncomms12993

ICER is requisite for Th17 differentiation

Nobuya Yoshida, Denis Comte, Masayuki Mizui, Kotaro Otomo, Florencia Rosetti, Tanya N. Mayadas, José C. Crispín, Sean J. Bradley, Tomohiro Koga, Michihito Kono, Maria P. Karampetsou, Vasileios C. Kyttaris, Klaus Tenbrock, George C. Tsokos

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48 Citations (Scopus)

Abstract

Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6-STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4⁺T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4⁺T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.

Original language	English
Article number	12993
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12993
Publication status	Published - 2016 Sept 29
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms12993

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@article{31fff5bea0da4b118a0ee88c2678d923,

title = "ICER is requisite for Th17 differentiation",

abstract = "Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6-STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.",

author = "Nobuya Yoshida and Denis Comte and Masayuki Mizui and Kotaro Otomo and Florencia Rosetti and Mayadas, {Tanya N.} and Crisp{\'i}n, {Jos{\'e} C.} and Bradley, {Sean J.} and Tomohiro Koga and Michihito Kono and Karampetsou, {Maria P.} and Kyttaris, {Vasileios C.} and Klaus Tenbrock and Tsokos, {George C.}",

note = "Funding Information: This work was supported by NIH grant (NIAID #R37AIO49954 to G.C.T., and #R01AR060849 to V.K.), 2011 Japan Sumitomo Life Welfare and Culture Foundation Subsidy for Invitation of Overseas Scientists (to N.Y.), 2013 Japan Society for the promotion of science postdoctoral fellowships for research abroad (to N.Y.) and SICPA Foundation grant (to D.C.). We thank Lucia Novelli and Robin Bosse for technical assistance. We thank Cox Terhorst for reviewing the manuscript critically and providing constructive comments. Publisher Copyright: {\textcopyright} 2016 The Author(s).",

year = "2016",

month = sep,

day = "29",

doi = "10.1038/ncomms12993",

language = "English",

volume = "7",

journal = "Nature communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - ICER is requisite for Th17 differentiation

AU - Yoshida, Nobuya

AU - Comte, Denis

AU - Mizui, Masayuki

AU - Otomo, Kotaro

AU - Rosetti, Florencia

AU - Mayadas, Tanya N.

AU - Crispín, José C.

AU - Bradley, Sean J.

AU - Koga, Tomohiro

AU - Kono, Michihito

AU - Karampetsou, Maria P.

AU - Kyttaris, Vasileios C.

AU - Tenbrock, Klaus

AU - Tsokos, George C.

N1 - Funding Information: This work was supported by NIH grant (NIAID #R37AIO49954 to G.C.T., and #R01AR060849 to V.K.), 2011 Japan Sumitomo Life Welfare and Culture Foundation Subsidy for Invitation of Overseas Scientists (to N.Y.), 2013 Japan Society for the promotion of science postdoctoral fellowships for research abroad (to N.Y.) and SICPA Foundation grant (to D.C.). We thank Lucia Novelli and Robin Bosse for technical assistance. We thank Cox Terhorst for reviewing the manuscript critically and providing constructive comments. Publisher Copyright: © 2016 The Author(s).

PY - 2016/9/29

Y1 - 2016/9/29

N2 - Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6-STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.

AB - Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6-STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.

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U2 - 10.1038/ncomms12993

DO - 10.1038/ncomms12993

M3 - Article

AN - SCOPUS:84989271289

SN - 2041-1723

VL - 7

JO - Nature communications

JF - Nature communications

M1 - 12993

ER -

ICER is requisite for Th17 differentiation

Abstract

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