Cyclic AMP underpins suppression by regulatory T cells

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 nuclearfactor 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. Keywords: CD4+ T cells r Costimulatory molecules r Gene regulation r Regulatory T (Treg) cells r Signal transduction IntroductionNaturally occurring CD4 + T regulatory (nTreg) cells are essential for maintaining peripheral tolerance; they prevent autoimmunity and limit chronic inflammatory diseases [1]. Immune responses, both protective and harmful, are principally mediated by T and B cells, which possess enormous diversity in antigen recognition, potent effector functions, and long-lasting immunologic memory. Every adaptive immune response involves the recruitment and activation of not only effector T and B cells but also nTreg cells, and the balance between effector and regulatory lymphocytes is criticalCorrespondence: Dr. Josef Bodor e-mail: bodor@uni-mainz.de for the proper control of adaptive immune responses. This balance is also critical for establishing or breaching tolerance against selfand nonself-antigens. Aside from peripheral conversion, the majority of nTreg cells are generated in the thymus with their frequency increasing from the late CD4 + CD8 + double positive to the CD4 + CD8 − single positive stage [2,3]. Remarkably, this coincides with the stage of thymic development during which human medullary thymocytes acquire cyclic AMP (cAMP) mediated expression of inducible cAMP early repressor (ICER) [4]. As ICER is a mediator of nTregcell suppression (see below and the section cAMP and Foxp3 direct ICER-mediated suppression), this suggests that competence to suppress develops in nTreg cells simultaneously with the ability of CD4 + T cells to be suppressed via upregulation of ICER.nTreg cells can have both beneficial effects, for example, preventing autoimmune diseases, and deleterious effects, for Eur. J. Immunol. 2012Immunol. . 42: 1375Immunol. -1384 example, impairing effective antitumor responses. Understanding the mechanisms of immunological self-tolerance, including those regulated by nTreg cells...

Regulatory T Cells in AKI

“…21,22 Lastly, Tregs transfer cAMP to activated CD4 + cells or antigenpresenting cells through gap junction intercellular communication to suppress target cell function. 23 Thus, Tregs use multiple diverse mechanisms to suppress inflammation and autoimmunity ( Figure 2). …”

Hunger-promoting hypothalamic neurons modulate effector and regulatory T-cell responses

“…Our results are also in line with the overall effect of sirtuins on the immune system (16) and suggest that AgRP neurons represent an important site of action of sirtuins to exert a systemic effect during low energy availability on the immune system. Finally, because the intracellular second messenger cAMP has a key role in mediating suppressive activity of Treg cells (39), in our system it would be interesting to monitor on hypothalamic neurons some cAMPactivating neurotransmitters such as the pituitary adenylate cyclase-activating polypeptide (39). Altered levels of such molecules could, at least in part, explain some of the results we observed in our AgRP-Sirt1 KO mice, particularly in the context of the observed reduced suppressive capacity of Treg cells.…”

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“…Analogous effect could be achieved by direct activation of adenylyl cyclase (AC) by forskolin or inhibition of phosphodiesterases (PDEs) responsible for degradation of cAMP e.g. by Rolipram [6,7]. In response to cAMP/PKA, ICER is induced (after 2-4 h of delay, necessary for ICER synthesis) in the Foxp3 neg Tcons and later ICER protein is enforced to the nucleus in response to cAMP/PKA where it may attenuate CCR5 expression in cAMP dependent fashion (Figure 2).…”

“…Our previous results indicate that PGE 2 may exert direct effects on downregulation of CCR5 expression in human peripheral blood monocytes (Figure 2). These preliminary studies suggest that in addition to ICER-mediated down regulation of interleukin 2 (IL-2) in autoreactive CD4 + conventional T cells (Tcons) [5][6][7] ICER could also transcriptionally attenuate expression of CCR5 receptor in the presence of PGE 2 ( Figure 2). Therefore genomewide analysis of the pulse treatment of dmPGE 2 for Tregs, Tcons, and HSCs and their consequent CCR5 downregulation along with downregulation of other chemokines and chemokine receptors (such as CXCR4) will be informative.…”