Cyclic AMP underpins suppression by regulatory T cells.
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.
Department of Molecular Pathology, Institute of Pathology, University of Würzburg, Würzburg, Germany. bodor@uni-mainz.de
Josef
J
Bodor
Tobias
T
Bopp
Martin
M
Vaeth
Matthias
M
Klein
Edgar
E
Serfling
Thomas
T
Hünig
Christian
C
Becker
Hansjörg
H
Schild
Edgar
E
Schmitt
D000818:Animals; D000938:Antigen-Presenting Cells / Q000502:physiology; D018122:B7-1 Antigen / Q000502:physiology; D018106:CD28 Antigens / Q000502:physiology; D060908:CTLA-4 Antigen / Q000502:physiology; D000242:Cyclic AMP / Q000502:physiology*; D051786:Cyclic AMP Response Element Modulator / Q000502:physiology; D051858:Forkhead Transcription Factors / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D007376:Interleukin-2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D050778:NFATC Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
D018122:B7-1 Antigen; D018106:CD28 Antigens; C497410:CREM protein, human; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D051786:Cyclic AMP Response Element Modulator; D000242:Cyclic AMP