ICER is requisite for Th17 differentiation.
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.
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Nobuya
N
Yoshida
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.|Division of Immunology and Allergy, Centre Hospitalier Universitaire Vaudois, 1011 Lausanne, Switzerland.
Denis
D
Comte
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Masayuki
http://orcid.org/0000-0003-2543-8108
M
Mizui
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Kotaro
K
Otomo
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Florencia
F
Rosetti
Center for Excellence in Vascular Biology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.
Tanya N
TN
Mayadas
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
José C
JC
Crispín
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Sean J
SJ
Bradley
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Tomohiro
T
Koga
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Michihito
M
Kono
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Maria P
MP
Karampetsou
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Vasileios C
VC
Kyttaris
Department of Pediatrics, Division of Allergology and Immunology, RWTH University of Aachen, 52056 Aachen, Germany.
Klaus
K
Tenbrock
Division of Rheumatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
George C
GC
Tsokos
Arthritis Rheum. 1997 Sep;40(9):1725
9324032
Nat Immunol. 2008 Nov;9(11):1297-306
18849990
J Exp Med. 2007 Jul 9;204(7):1543-51
17591856
Cell. 1991 Feb 22;64(4):739-49
1847666
Nat Immunol. 2007 Dec;8(12):1390-7
17994024
J Immunol. 2014 Jan 1;192(1):475-83
24298014
J Clin Invest. 2015 Jun;125(6):2220-7
25961450
Nephrology (Carlton). 2010 Aug;15(5):513-21
20649870
Dermatol Clin. 2015 Jan;33(1):13-23
25412780
Clin Exp Immunol. 2015 Jul;181(1):76-86
25817470
Immunity. 2012 Dec 14;37(6):1104-15
23123062
Proc Natl Acad Sci U S A. 1996 Apr 16;93(8):3536-41
8622971
J Biol Chem. 2011 Dec 16;286(50):43437-46
22025620
N Engl J Med. 2011 Dec 1;365(22):2110-21
22129255
Cell. 1992 Feb 7;68(3):411-4
1739963
Annu Rev Immunol. 2009;27:485-517
19132915
Oncotarget. 2015 Nov 17;6(36):38538-51
26459392
Curr Opin Rheumatol. 2010 Sep;22(5):499-503
20592603
J Leukoc Biol. 2001 Jun;69(6):1053-9
11404394
Arthritis Rheum. 1992 Jun;35(6):630-40
1599520
J Immunol. 2014 Jul 15;193(2):540-3
24920843
Cytokine. 2015 Dec;76(2):280-7
26073684
J Immunol. 2010 May 1;184(9):4605-9
20308633
J Mol Cell Biol. 2012 Apr;4(2):121-3
22355096
J Immunol. 2008 Dec 15;181(12):8761-6
19050297
Nat Immunol. 2005 Nov;6(11):1123-32
16200070
J Immunol. 2012 Apr 15;188(8):3567-71
22422882
Nat Commun. 2015 Jun 02;6:7216
26031354
Cell. 2012 Oct 12;151(2):289-303
23021777
J Immunol. 2009 Feb 1;182(3):1500-8
19155497
J Clin Invest. 2014 May;124(5):2234-45
24667640
Biochem J. 2013 Dec 15;456(3):463-73
24007532
Nat Immunol. 2005 Nov;6(11):1133-41
16200068
Autoimmunity. 2007 Feb;40(1):1-8
17364491
Nature. 1996 Mar 14;380(6570):162-5
8600391
J Vis Exp. 2011 Apr 09;(50):null
21505412
Cell Signal. 2011 Jun;23(6):1009-16
21130867
Nihon Shinkei Seishin Yakurigaku Zasshi. 2011 Apr;31(2):79-80
21618901
J Interferon Cytokine Res. 2011 Oct;31(10):769-79
21877904