Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression

Muayad Almahariq, Fang C. Mei, Hui Wang, Anthony T. Cao, Suxia Yao, Lynn Soong, Jiaren Sun, Yingzi Cong, Ju Chen, Xiaodong Cheng

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)295-303
Number of pages9
JournalBiochemical Journal
Volume465
DOIs
StatePublished - Jan 15 2015

Keywords

  • CAMP
  • EPAC1
  • Gap Junction
  • Guanine-nucleotide-exchange factor
  • Regulatory T-cell
  • STAT3
  • TGF-β1

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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