Cyclic AMP-Responsive Element-Binding Protein (CREB) is Critical in Autoimmunity by Promoting Th17 but Inhibiting Treg Cell Differentiation

Xiaohu Wang; Lu Ni; Dehui Chang; Huiping Lu; Yu Jiang; Byung-Seok Kim; Aibo Wang; Xindong Liu; Bo Zhong; Xuexian Yang; Chen Dong

doi:10.1016/j.ebiom.2017.10.010

Cyclic AMP-Responsive Element-Binding Protein (CREB) is Critical in Autoimmunity by Promoting Th17 but Inhibiting Treg Cell Differentiation

EBioMedicine. 2017 Nov:25:165-174. doi: 10.1016/j.ebiom.2017.10.010. Epub 2017 Oct 12.

Authors

Xiaohu Wang¹, Lu Ni², Dehui Chang², Huiping Lu², Yu Jiang², Byung-Seok Kim³, Aibo Wang³, Xindong Liu⁴, Bo Zhong⁵, Xuexian Yang⁶, Chen Dong⁷

Affiliations

¹ Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].
² Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China.
³ Department of Immunology, M.D. Anderson Cancer Center, Houston, TX 77030, USA.
⁴ Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China.
⁵ School of Life Sciences, Wuhan University, Wuhan 430072, China.
⁶ Department of Molecular Genetics and Microbiology, University of New Mexico School of Medicine, Albuquerque, NM, USA.
⁷ Institute for Immunology and School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address: [email protected].

Abstract

The molecular mechanisms that govern differential T cell development into pro-inflammatory Th17 vs. regulatory T (Treg) cells remain unclear. Here, we show that selective deletion of CREB in T cells or Th17 cells impaired Th17 cell differentiation in vitro and in vivo, and led to resistance to autoimmune diseases. Mechanistically, CREB, activated by CD3-PKC-ϴ signaling, plays a key role in regulating Th17 cell differentiation, at least in part through directly binding to the Il17-Il17f gene locus. Unexpectedly, although dispensable for FOXP3 expression and for the homeostasis and suppressive function of thymus-derived Treg cells, CREB negatively regulates the survival of TGF-β-induced Treg cells, and deletion of CREB resulted in increased FOXP3+ Treg cells in the intestine and protection in a colitis model. Thus, CREB is critical in autoimmune diseases by promoting Th17 cell and inhibiting de novo Treg cell generation.

Keywords: Autoimmune diseases; CREB; Th17 cells; Treg cells.

MeSH terms

Animals
Autoimmune Diseases / genetics*
Autoimmune Diseases / immunology
Autoimmune Diseases / pathology
CD3 Complex / genetics
CD3 Complex / immunology
Cell Differentiation / genetics
Cell Differentiation / immunology
Cyclic AMP Response Element-Binding Protein / genetics*
Cyclic AMP Response Element-Binding Protein / immunology
Forkhead Transcription Factors / genetics*
Forkhead Transcription Factors / immunology
Humans
Interleukin-17 / genetics*
Interleukin-17 / immunology
Lymphocyte Activation
Mice
Nuclear Receptor Subfamily 1, Group F, Member 3 / genetics
Protein Kinase C-theta / genetics
Protein Kinase C-theta / immunology
T-Lymphocytes, Regulatory / immunology
Th17 Cells / immunology
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / immunology

Substances

CD3 Complex
Creb1 protein, mouse
Cyclic AMP Response Element-Binding Protein
Forkhead Transcription Factors
Foxp3 protein, mouse
IL17A protein, human
Interleukin-17
Nuclear Receptor Subfamily 1, Group F, Member 3
RORC protein, human
Transforming Growth Factor beta
Protein Kinase C-theta

Abstract

MeSH terms

Substances

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