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

Bodor, Josef; Fehérvari, Zoltán; Diamond, Betty; Sakaguchi, Shimon

doi:10.1002/eji.200636510

Cited by 56 publications

(67 citation statements)

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“…12,33 This finding was later confirmed by the identification of a cAMP-inducible transcriptional repressor that is termed the 'inducible cAMP early repressor'. 36,37 Inducible cAMP early repressor attenuates IL-2 expression by competitively binding to the transcription factor cAMP response element-binding protein. 38 Our study confirms the correlation between the cAMP signaling pathway and CY treatment, and our findings appear to contradict the clinical efficacy of the combination of chemotherapy and immunotherapy for the treatment of lymphoma patients.…”

Section: Western Blot Analysismentioning

confidence: 99%

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Dou

Liu

et al. 2012

Cell Mol Immunol

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Lymphoma cells mobilize many mechanisms to evade the immune system. There is substantial evidence that CD4 1 CD25 1 regulatory T cells (Tregs) play a key role in the control of immune evasion. Tregs can transfer cyclic adenosine monophosphate (cAMP) to effector T cells, suggesting an association between Tregs' immune-evasion role and the intracellular cAMP pathway. In this study, we used A20 B-cell lymphoma mice as aggressive tumor models to investigate the mechanism of the depletion of Tregs by low-dose cyclophosphamide (CY, 20 mg/kg). The tumor-bearing mice had longer survival times and slower tumor growth rates following treatment with CY, but its effects were temporary. Along with the depletion of Tregs by low-dose CY treatment, the expression of interleukin-2 (IL-2) in T effector cells increased, and intracellular cAMP concentrations in immune cells decreased. Our study demonstrates the ability of low-dose CY to reverse Tregs-mediated immune evasion in a mouse model. The changes in intracellular cAMP concentrations correlated with the upregulation of effector T cells and the downregulation of Tregs, indicating the close association of cAMP analogs and low-dose CY in the immune therapy of B-cell lymphoma.

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Section: Western Blot Analysismentioning

confidence: 99%

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Dou

Liu

et al. 2012

Cell Mol Immunol

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“…A critical role of NFAT factors for inhibitory complex formation is further strengthened by observations indicating that combined NFATc2/c3 deficiency rendered conventional CD4 + T cells unresponsive to suppression, although normal nTreg development was detected in those mice (11). Moreover, targeting ICER/ CREM in RNAi and antisense RNA approaches antagonized the nTreg-mediated suppression and/or inhibition of IL-2 production in conventional CD4 + T cells, rendering these effector T cells refractory to suppression (7,12).…”

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confidence: 95%

“…Inhibition of cAMP degradation by the phosphodiesterase (PDE)-4 inhibitor rolipram enhanced nTreg-mediated suppression of effector CD4 + T cells both in vitro and in vivo (6). Unlike conventional CD4 + T cells, which express relatively low ICER/CREM levels, nTregs show a marked increase in inducible cAMP early repressor (ICER)/ cAMP response modulator (CREM) mRNA and protein levels because of the enhancing effects of Foxp3 (7). ICER binds specifically to multiple nuclear factor of activated T cell (NFAT)/ AP-1 sites within the Il2 promoter (8), which correlates with a strong decrease in the number of IL-2-expressing effector CD4 + T cells (7).…”

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confidence: 99%

“…Unlike conventional CD4 + T cells, which express relatively low ICER/CREM levels, nTregs show a marked increase in inducible cAMP early repressor (ICER)/ cAMP response modulator (CREM) mRNA and protein levels because of the enhancing effects of Foxp3 (7). ICER binds specifically to multiple nuclear factor of activated T cell (NFAT)/ AP-1 sites within the Il2 promoter (8), which correlates with a strong decrease in the number of IL-2-expressing effector CD4 + T cells (7). It was proposed that such composite NFAT/ AP-1 binding motifs generate NFAT/Foxp3 inhibitor complexes, which suppress the Il2 gene expression in nTreg cells (9).…”

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confidence: 99%

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Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1)

Vaeth¹,

Gogishvili

Bopp

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Inducible cAMP early repressor (ICER) is a transcriptional repressor, which, because of alternate promoter use, is generated from the 3′ region of the cAMP response modulator (Crem) gene. Its expression and nuclear occurrence are elevated by high cAMP levels in naturally occurring regulatory T cells (nTregs). Using two mouse models, we demonstrate that nTregs control the cellular localization of ICER/CREM, and thereby inhibit IL-2 synthesis in conventional CD4 + T cells. Ablation of nTregs in depletion of regulatory T-cell (DEREG) mice resulted in cytosolic localization of ICER/CREM and increased IL-2 synthesis upon stimulation. Direct contacts between nTregs and conventional CD4 + T cells led to nuclear accumulation of ICER/CREM and suppression of IL-2 synthesis on administration of CD28 superagonistic (CD28SA) Ab. In a similar way, nTregs communicated with B cells and induced the cAMPdriven nuclear localization of ICER/CREM. High levels of ICER suppressed the induction of nuclear factor of activated T cell c1 (Nfatc1) gene in T cells whose inducible Nfatc1 P1 promoter bears two highly conserved cAMP-responsive elements to which ICER/ CREM can bind. These findings suggest that nTregs suppress T-cell responses by the cAMP-dependent nuclear accumulation of ICER/ CREM and inhibition of NFATc1 and IL-2 induction.adenosin 3′,5′-cyclic monophospate | transcription | lymphocytes

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“…CTLA4 binds to CD80 or CD86 with greater affinity than CD28 to block costimulatory signals, leading to inhibition of cell cycle progression and IL-2 production (4). The blockade of CTLA4 by antibody prevents the accumulation of inducible cyclic AMP (cAMP) early repressor and cAMP response element modulator, and leads to the rescue of IL-2 expression (5,6). cAMP has a similar inhibitory effect on proliferation and IL-2 production in T cells (7,8).…”

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confidence: 99%

Regulation of Cytotoxic T Lymphocyte Antigen 4 by Cyclic AMP

Lin

Murray

et al. 2013

Am J Respir Cell Mol Biol

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Recent studies indicate that cyclic AMP (cAMP) induces cytotoxic T lymphocyte antigen (CTLA) 4. CTLA4 is expressed in T cells, and is a negative regulator of T cell activation. CTLA4 expression is regulated by T cell receptor plus CD28 (adaptive immune signaling) at both the transcriptional and post-transcriptional level. Here, we examine the pathways by which cAMP regulates CTLA4 expression, focusing on transcriptional activation. Elevating intracellular cAMP levels by cellpermeable cAMP analogs, the adenylyl cyclase activator, forskolin, or phosphodiesterase inhibitors increases CTLA4 mRNA expression in EL4 murine T cells and primary CD41 T cells. Activation of protein kinase A (using the protein kinase A-selective agonist, N6-phenyladenosine-cAMP), but not exchange proteins activated by cAMP (using the exchange proteins activated by cAMP-selective 8-pCPT-2Me-cAMP), increases CTLA4 promoter activity. Mutation constructs of the CTLA4 promoter uncover an enhancer binding site located within the 2150 to 2130 bp region relative to the transcription start site. Promoter analysis and chromatin immunoprecipitation assays suggest that cAMP response element-binding is a putative transcription factor induced by cAMP. We have previously shown that CTLA4 mediates decreased pulmonary inflammation in an LPSinduced murine model of acute lung injury (ALI). We observed that LPS can induce CTLA4 transcription via the same cAMP-inducible promoter region. The immunosuppressant, rapamycin, decreases cAMP and LPS-induced CTLA4 transcription in vitro. In vivo, LPS induces cAMP accumulation in bronchoalveolar lavage fluid, bronchoalveolar lavage cells, and lung tissues in ALI. We demonstrate that rapamycin decreases cAMP accumulation and CTLA4 expression in ALI. Together, these data suggest that cAMP may negatively regulate pulmonary inflammatory responses in vivo and in vitro by altering CTLA4 expression.Keywords: cytotoxic T lymphocyte antigen 4; cAMP; acute lung injury; protein kinase A; rapamycin Activated T cells express negative regulators, including cytotoxic T lymphocyte antigen (CTLA) 4, a negative regulator of T cell activation (1-3). CTLA4 binds to CD80 or CD86 with greater affinity than CD28 to block costimulatory signals, leading to inhibition of cell cycle progression and IL-2 production (4). The blockade of CTLA4 by antibody prevents the accumulation of inducible cyclic AMP (cAMP) early repressor and cAMP response element modulator, and leads to the rescue of IL-2 expression (5, 6). cAMP has a similar inhibitory effect on proliferation and IL-2 production in T cells (7,8).cAMP is an important second messenger in many biological processes. cAMP is synthesized from ATP by adenylyl cyclase and degraded by phosphodiesterase (PDE). In physiological conditions, a wide range of signaling molecules, such as epinephrine, glucagon, and prostaglandin E2, increase cAMP accumulation via G protein-coupled receptor. cAMP can also be activated in response to microbial challenges or LPS (9). The main targets of cAMP are protein kinase ...

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

Cited by 56 publications

References 54 publications

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Cyclic adenosine monophosphate involvement in low-dose cyclophosphamide-reversed immune evasion in a mouse lymphoma model

Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1)

Regulation of Cytotoxic T Lymphocyte Antigen 4 by Cyclic AMP

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