期刊
BIOCHEMICAL JOURNAL
卷 456, 期 -, 页码 463-473出版社
PORTLAND PRESS LTD
DOI: 10.1042/BJ20130064
关键词
cyclic nucleotide phosphodiesterase; immune tolerance; immunosuppression; inducible cAMP early repressor (ICER); T-cell proliferation
资金
- National Multiple Sclerosis Society [RG 4544A1/1, RG 4070A6]
- institutional start-up funds
- Connecticut Breast Health Initiative
- CT Department of Public Health
- Smart Family Foundation
- Lea's Foundation for Leukemia Research
- National Institutes of Health [1R56 A1072533-01 Al, R01 AR046542]
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.
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