title: Exchange protein directly activated by cAMP modulates regulatory T-cell-mediated immunosuppression.
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.
authors.affiliation: *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.
authors.forename: Muayad
authors.initials: M
authors.lastname: Almahariq
authors.affiliation: *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.
authors.forename: Fang C
authors.initials: FC
authors.lastname: Mei
authors.affiliation: *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.
authors.forename: Hui
authors.initials: H
authors.lastname: Wang
authors.affiliation: ‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
authors.forename: Anthony T
authors.initials: AT
authors.lastname: Cao
authors.affiliation: ‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
authors.forename: Suxia
authors.initials: S
authors.lastname: Yao
authors.affiliation: ‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
authors.forename: Lynn
authors.initials: L
authors.lastname: Soong
authors.affiliation: ‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
authors.forename: Jiaren
authors.initials: J
authors.lastname: Sun
authors.affiliation: ‡Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, U.S.A.
authors.forename: Yingzi
authors.initials: Y
authors.lastname: Cong
authors.affiliation: ║Department of Medicine, University of California, La Jolla, CA, U.S.A.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: *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.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Cheng
mesh_terms: D000818:Animals; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology; D051901:Smad4 Protein / Q000235:genetics / Q000276:immunology; D051906:Smad7 Protein / Q000235:genetics / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000276:immunology
chemical_list: C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D050796:STAT3 Transcription Factor; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; C494087:Stat3 protein, mouse; C508961:Tgfb1 protein, mouse; D053773:Transforming Growth Factor beta1