Cyclic Adenosine 5′-Monophosphate and Calcium Induce CD152 (CTLA-4) Up-Regulation in Resting CD4+ T Lymphocytes

Vendetti, Silvia; Riccomi, Antonella; Sacchi, Alessandra; Gatta, Lucia; Pioli, Claudio; Magistris, Maria Teresa De

doi:10.4049/jimmunol.169.11.6231

Cited by 42 publications

(46 citation statements)

References 30 publications

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“…Additional support for this mechanism is provided by tight link between cAMP-mediated induction of CTLA-4 and ICER in CD4 + T cells [6,11,13]. This is consistent with our data indicating that CTLA-4 blockade can disrupt accumulation of ICER/CREM, thus releasing contact-dependent T R -mediated suppression.…”

Section: Discussionsupporting

confidence: 91%

“…Remarkably, GILZ is coexpressed in T cells with GITR [50]. This relationship appears reminiscent of cAMP-mediated induction of ICER and CTLA-4 [6,13]. Remarkably, in T R assays with B7-deficient CD25 -responders residual suppression is still detectable (Supporting Information Fig.…”

Section: Discussionmentioning

confidence: 86%

“…Importantly, signaling through the second messenger cyclic adenosine monophosphate (cAMP) up-regulates CTLA-4 in resting CD4 + T lymphocytes [6]. Furthermore, CTLA-4 increases T cell motility and overrides TCR induced stop signals required for stable conjugate formation between T cells and antigen presenting cells (APC) [7].…”

Section: Introductionmentioning

confidence: 99%

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ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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Here, we report that inducible cAMP early repressor/cAMP response element modulator (ICER/CREM) is induced early in CD25 + CD4 + regulatory T cell (T R ) assays mainly in activated Foxp3 -effector T cells and this induction correlates with sharp decrease in number of IL-2-expressing T cells. Importantly, RNAi targeting of ICER/CREM in responder CD25 -CD4 + T cells antagonizes T R -mediated suppression. Moreover, forced expression of Foxp3 in naive CD25 -T cells induces constitutive expression of ICER/ CREM in T cells with a regulatory phenotype. Foxp3 facilitates expression of ICER/ CREM both in Foxp3 transductants as well as CD25 -responder T cells suggesting that induction of T R function in suppression assays may utilize contact-dependent interaction. Indeed, CTLA-4 blockade or use of B7-deficient CD25 -responder T cells prevents ICER/CREM accumulation and leads to the rescue of IL-2 expression. Therefore, we propose that CTLA-4 binding to B7 ligands expressed on activated ligandbearing Foxp3 -effector T cells results in ICER/CREM-mediated transcriptional attenuation of IL-2. Collectively, these data suggest that Foxp3 expression in T R cells imposes suppression in contact-dependent fashion by induction of constitutive ICER/ CREM expression in activated CD25 + Foxp3 -T cell effectors thus preventing them from producing IL-2.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 86%

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ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

et al. 2007

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“…CTLA4 gene expression was determined by RT-PCR, as previously described (20). Primers used were designed to amplify the entire coding sequence of CTLA4 (5Ј-ATGGCTTGCCTTGGATTTCAGCGGCACA AGG-3Ј and 5Ј-TCAATTGATGGGAATAAAATAAGGCTGAAATTGC-3Ј).…”

Section: Determination Of Gene Expressionmentioning

confidence: 99%

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

Pozo

Anderson

González‐Rey

2009

The Journal of Immunology

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T regulatory cells (Tregs) are instrumental in the maintenance of immunological tolerance. Although Treg-based immunotherapy proved successful in preclinical autoimmunity and transplantation, factors involved in the generation of human Ag-specific Tregs are poorly known. In this study, we show that treatment of human CD4+CD25− T cells with the cytokine-like vasoactive intestinal peptide (VIP) during in vitro stimulation induces an anergic FoxP3+CD4+CD25high T cell subset displaying potent regulatory activities against allospecific effector T cells, irrespective of the presence of naturally occurring Tregs. VIP-tolerant T cells are characterized by incapability to progress to S phase of cell cycle during stimulation with HLA-disparate APCs by negatively affecting the synthesis of cyclins D3 and E, the activation of cyclin-dependent kinases (cdk)2 and cdk4, and the down-regulation of the cdk inhibitor p27kip1. VIP interaction with the type 1 VIP receptor and subsequent activation of cAMP/protein kinase A pathway play a major role in all these effects. Moreover, VIP-tolerant T cells protect against acute graft-vs-host disease in a mouse model of allogeneic bone marrow transplantation. The infusion of VIP-tolerant T cells together with the graft significantly reduces the clinical signs and mortality rate typical of the graft-vs-host disease. These effects are mediated by impairing allogeneic haplotype-specific responses of donor CD4+ cells in the transplanted animals. Our results suggest that including alloantigen-specific VIP-generated Tregs may be a valuable tool in therapeutic interventions to promote immunotolerance toward allogeneic grafts and to reduce the need of general immunosuppressive drugs.

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“…Recently, it has been reported that PGE 2 has this property (54). This agent up-regulates cAMP, and this element also can up-regulate CTLA-4 (55). Another group has reported that immature APCs whose maturation was blocked by a proteosome inhibitor also induce CD4 ϩ cells to express FoxP3 and develop suppressive effects (56).…”

Section: Cd25mentioning

confidence: 99%

TGF-β Requires CTLA-4 Early after T Cell Activation to Induce FoxP3 and Generate Adaptive CD4+CD25+ Regulatory Cells

Zheng

Wang

Stohl

et al. 2006

The Journal of Immunology

263

173

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Although positive CD28 costimulation is needed for the generation of natural CD4+CD25+ regulatory T cells, we report that negative CTLA-4 costimulation is necessary for generating phenotypically and functionally similar adaptive CD4+CD25+ suppressor cells. TGF-β could not induce CD4+CD25− cells from CTLA-4−/− mice to express normal levels of FoxP3 or to develop suppressor activity. Moreover, blockade of CTLA-4 following activation of wild-type CD4+ cells abolished the ability of TGF-β to induce FoxP3-expressing mouse suppressor cells. TGF-β accelerated expression of CTLA-4, and time course studies suggested that CTLA-4 ligation of CD80 shortly after T cell activation enables TGF-β to induce CD4+CD25− cells to express FoxP3 and develop suppressor activity. TGF-β also enhanced CD4+ cell expression of CD80. Thus, CTLA-4 has an essential role in the generation of acquired CD4+CD25+ suppressor cells in addition to its other inhibitory effects. Although natural CD4+CD25+ cells develop normally in CTLA-4−/− mice, the lack of TGF-β-induced, peripheral CD4+CD25+ suppressor cells in these mice may contribute to their rapid demise.

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Cyclic Adenosine 5′-Monophosphate and Calcium Induce CD152 (CTLA-4) Up-Regulation in Resting CD4+ T Lymphocytes

Cited by 42 publications

References 30 publications

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

ICER/CREM‐mediated transcriptional attenuation of IL‐2 and its role in suppression by regulatory T cells

Induction of Alloantigen-Specific Human T Regulatory Cells by Vasoactive Intestinal Peptide

TGF-β Requires CTLA-4 Early after T Cell Activation to Induce FoxP3 and Generate Adaptive CD4+CD25+ Regulatory Cells

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