Cyclic AMP underpins suppression by regulatory T cells

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Abstract
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/α (NFATc1/α) 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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