Regulatory T cells and cAMP suppress effector T cells independently of PKA-CREM/ICER: a potential role for Epac

cAMP signaling is both a major pathway as well as a key therapeutic target for inducing immune tolerance and is involved in regulatory T cell (Treg 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 leading to the induction of the transcription factor inducible cAMP early repressor (ICER). Here, we examined CD4+CD25- effector T cell (Teff cell) and CD4+CD25+ Treg cell immune responses in cAMP responsive element modulator (Crem) 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 pharmacologic 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 exchange protein directly activated by cAMP (Epac) suppressed Teff cells. Treg cells expressed low levels of all cyclic nucleotide phosphodiesterase (Pde) genes tested but high levels of Epac. These data identify ICER as a redundant mediator of Treg cell and cAMP action on Teff cells and suggest that Epac may function as an alternative effector to promote cAMP-dependent Teff cell suppression.

Source: BJ Cell - September 5, 2013 Category: Biochemistry Authors: A G. Vang, W Housley, H Dong, C Basole, S Z. Ben-Sasson, B E. Kream, P M. Epstein, R B. Clark, S Brocke Tags: BJ Signal Source Type: research