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Cyclic AMP underpins suppression by regulatory T cells

Journal

EUROPEAN JOURNAL OF IMMUNOLOGY
Volume 42, Issue 6, Pages 1375-1384

Publisher

WILEY
DOI: 10.1002/eji.201141578

Keywords

CD4+T cells; Costimulatory molecules; Gene regulation; Regulatory T (Treg) cells; Signal transduction

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Elevated levels of intracellular cyclic adenosine monophosphate (cAMP) in naturally occurring T regulatory (nTreg) cells play a key role in nTreg-cell-mediated suppression. Upon contact with nTreg cells, cAMP is transferred from nTreg cells into activated target CD4+ T cells and/or antigen-presenting cells (APCs) via gap junctions to suppress CD4+ T-cell function. cAMP facilitates the expression and nuclear function of a potent transcriptional inhibitor, inducible cAMP early repressor (ICER), resulting in ICER-mediated suppression of interleukin-2 (IL-2). Furthermore, ICER inhibits transcription of nuclear factor of activated T cell c1/a (NFATc1/a) and forms inhibitory complexes with preexisting NFATc1/c2, thereby inhibiting NFAT-driven transcription, including that of IL-2. In addition to its suppressive effects mediated via ICER, cAMP can also modulate the levels of surface-expressed cytotoxic T lymphocyte antigen-4 (CTLA-4) and its cognate B7 ligands on conventional CD4+ T cells and/or APCs, fine-tuning suppression. These cAMP-driven nTreg-cell suppression mechanisms are the focus of this review.

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