title: Regulatory T-cells and cAMP suppress effector T-cells independently of PKA-CREM/ICER: a potential role for Epac.
abstract: cAMP signalling is both a major pathway as well as a key therapeutic target for inducing immune tolerance and is involved in Treg cell (regulatory T-cell) function. To achieve potent immunoregulation, cAMP can act through several downstream effectors. One proposed mechanism is that cAMP-mediated suppression, including immunosuppression by Treg cells, results from activation of PKA (protein kinase A) leading to the induction of the transcription factor ICER (inducible cAMP early repressor). In the present study, we examined CD4(+)CD25(-) Teff cell (effector T-cell) and CD4(+)CD25(+) Treg cell immune responses in Crem (cAMP-response-element modulator) gene-deficient mice which lack ICER (Crem(-/-)/ICER-deficient mice). ICER deficiency did not significantly alter the frequency or number of Treg cells and Teff cells. Treg cells or a pharmacological increase in cAMP suppressed Teff cells from Crem(+/+) and Crem(-/-)/ICER-deficient mice to an equivalent degree, demonstrating that ICER is dispensable in these functions. Additionally, activating the cAMP effector Epac (exchange protein directly activated by cAMP) suppressed Teff cells. Treg cells expressed low levels of all cyclic nucleotide Pde (phosphodiesterase) genes tested, but high levels of Epac. These data identify ICER as a redundant mediator of Treg cells and cAMP action on Teff cells and suggest that Epac may function as an alternative effector to promote cAMP-dependent Teff cell suppression.
authors.affiliation: *Department of Immunology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030-6125, U.S.A.
authors.forename: Amanda G
authors.initials: AG
authors.lastname: Vang
authors.forename: William
authors.initials: W
authors.lastname: Housley
authors.forename: Hongli
authors.initials: H
authors.lastname: Dong
authors.forename: Chaitali
authors.initials: C
authors.lastname: Basole
authors.forename: Shlomo Z
authors.initials: SZ
authors.lastname: Ben-Sasson
authors.forename: Barbara E
authors.initials: BE
authors.lastname: Kream
authors.forename: Paul M
authors.initials: PM
authors.lastname: Epstein
authors.forename: Robert B
authors.initials: RB
authors.lastname: Clark
authors.forename: Stefan
authors.initials: S
authors.lastname: Brocke
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000502:physiology; D000242:Cyclic AMP / Q000235:genetics / Q000276:immunology*; D051786:Cyclic AMP Response Element Modulator / Q000235:genetics / Q000276:immunology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000276:immunology*; D005260:Female; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology*
chemical_list: C497411:Crem protein, mouse; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases