The cAMP signalling pathway plays an essential role in immune functions. In the present study we examined the role of the cAMP/EPAC1 (exchange protein directly activated by cAMP) axis in regulatory T-cell (Treg)-mediated immunosuppression using genetic and pharmacological approaches. Genetic deletion of EPAC1 in Tregs and effector T-cells (Teffs) synergistically attenuated Treg-mediated suppression of Teffs. Mechanistically, EPAC1 inhibition enhanced activation of the transcription factor STAT3 (signal transducer and activator of transcription 3) and up-regulated SMAD7 expression while down-regulating expression of SMAD4. Consequently, CD4+ T-cells were desensitized to transforming growth factor (TGF) β1, a cytokine employed by Tregs to exert a broad inhibitory function within the immune system. Furthermore, deletion of EPAC1 led to production of significant levels of ovalbumin IgG antibodies in a low-dose, oral-tolerance mouse model. These in vivo observations are consistent with the finding that EPAC1 plays an important role in Treg-mediated suppression. More importantly, pharmacological inhibition of EPAC1 using an EPAC-specific inhibitor recapitulates the EPAC1 deletion phenotype both in vivo and in vitro. The results of the present study show that EPAC1 boosts Treg-mediated suppression, and identifies EPAC1 as a target with broad therapeutic potential because Tregs are involved in numerous pathologies, including autoimmunity, infections and a wide range of cancers.
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Research Article|
January 06 2015
Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression
Muayad Almahariq;
Muayad Almahariq
*Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, U.S.A.
†Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, U.S.A.
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Fang C. Mei;
Fang C. Mei
*Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, U.S.A.
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Hui Wang;
Hui Wang
*Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, U.S.A.
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Anthony T. Cao;
Anthony T. Cao
‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
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Suxia Yao;
Suxia Yao
‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
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Lynn Soong;
Lynn Soong
‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
§Department of Pathology, University of Texas Medical Branch, Galveston, TX, U.S.A.
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Jiaren Sun;
Jiaren Sun
‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
§Department of Pathology, University of Texas Medical Branch, Galveston, TX, U.S.A.
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Yingzi Cong;
Yingzi Cong
‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
§Department of Pathology, University of Texas Medical Branch, Galveston, TX, U.S.A.
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Ju Chen;
Ju Chen
║Department of Medicine, University of California, La Jolla, CA, U.S.A.
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Xiaodong Cheng
Xiaodong Cheng
1
*Department of Integrative Biology and Pharmacology, Texas Therapeutics Institute, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, U.S.A.
1To whom correspondence should be addressed (email xiaodong.cheng@uth.tmc.edu).
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Publisher: Portland Press Ltd
Received:
July 29 2014
Revision Received:
October 09 2014
Accepted:
October 23 2014
Accepted Manuscript online:
October 23 2014
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2015 Biochemical Society
2015
Biochem J (2015) 465 (2): 295–303.
Article history
Received:
July 29 2014
Revision Received:
October 09 2014
Accepted:
October 23 2014
Accepted Manuscript online:
October 23 2014
Citation
Muayad Almahariq, Fang C. Mei, Hui Wang, Anthony T. Cao, Suxia Yao, Lynn Soong, Jiaren Sun, Yingzi Cong, Ju Chen, Xiaodong Cheng; Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression. Biochem J 15 January 2015; 465 (2): 295–303. doi: https://doi.org/10.1042/BJ20140952
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