Human CD4+ T lymphocytes with increased intracellular cAMP levels exert regulatory functions by releasing extracellular cAMP

Vendetti, Silvia; Patrizio, Mario; Riccomi, Antonella; Magistris, Maria Teresa De

doi:10.1189/jlb.0106072

Cited by 26 publications

(26 citation statements)

References 46 publications

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“…It is known that the second messenger cAMP can have immunosuppressive effects on T and B lymphocytes (28,32,38). We confirmed these findings, showing that CT, LT, FSK, and cAMP analogues inhibited the proliferation of B cells induced by polyclonal stimuli.…”

Section: Discussionsupporting

confidence: 80%

Cholera Toxin andEscherichia coliHeat-Labile Enterotoxin, but Not Their Nontoxic Counterparts, Improve the Antigen-Presenting Cell Function of Human B Lymphocytes

Negri¹,

Pinto²,

Vendetti³

et al. 2009

Infect Immun

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The development of effective mucosal vaccines has been hindered by the lack of useful adjuvants and our limited knowledge of their modes of action. Cholera toxin (CT) from Vibrio cholerae and Escherichia coli heat-labile enterotoxin (LT) are potent immunological adjuvants, as indicated by mouse vaccine studies, although their mechanisms of action are not fully understood. These toxins are holotoxins composed of an enzymatically active A subunit that is noncovalently linked to a pentamer of B subunits binding a variety of galactose-containing molecules present in the plasma membranes of eukaryotic cells. CT binds mostly to the ganglioside GM1, which is believed to be the major toxin receptor, whereas LT binds not only to GM1 but also to other glycosphingolipids. Once internalized, the A subunit ADP ribosylates the ␣ subunit of the GTP-binding regulatory protein Gs, thereby inducing permanent adenylate cyclase activation, resulting in an increase in the level of intracellular cyclic AMP (cAMP) (reviewed in reference 34).The potentiation of antigen-presenting cell (APC) function is a major aspect of adjuvant action, and it has been shown that CT and LT induce maturation of both murine dendritic cells (DC) (26, 36) and human DC (5,14,15). Several studies demonstrated the ability of these toxins to promote B-cell isotype switch differentiation in mice (19,27) and upregulation of activation markers in both murine and human B cells (2-4). While these toxins are potent adjuvants, their toxicity makes them unsuitable for human use. For this reason, a number of investigators have tried to develop nontoxic derivatives of CT and LT that retain adjuvanticity either by removing the A domain or by rendering it enzymatically inactive by site-directed mutagenesis (34). Although the current data suggest that the enzymatic activity of CT and LT holotoxins is responsible for the most potent adjuvant activity, a number of reports proposed that there are multiple immune modulating pathways that are triggered by CT and LT, including mechanisms independent of ADP ribosyltransferase activity (11,13,30,33,42). Numerous studies have suggested that engagement of the ganglioside GM1, the major receptor for CT and LT, is required for the ability of these molecules to modulate immune responses (22,31). Recently, workers demonstrated that in the absence of the toxic A subunit, the B subunit of CT (CT-B) induces intracellular signaling associated with the in vitro activation of murine B cells and macrophages (37).The majority of these studies have been performed with murine cells and have confirmed the in vivo adjuvanticity of nontoxic compounds, such as CT-B and LTK63, a mutant of LT lacking the ADP ribosyltransferase enzymatic activity, when they were mucosally delivered into animals, even if the immune responses observed in the in vivo studies were usually weaker than those induced by the wild-type toxins (6, 11, 20,

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Section: Discussionsupporting

confidence: 80%

Cholera Toxin andEscherichia coliHeat-Labile Enterotoxin, but Not Their Nontoxic Counterparts, Improve the Antigen-Presenting Cell Function of Human B Lymphocytes

Negri¹,

Pinto²,

Vendetti³

et al. 2009

Infect Immun

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“…Elevated cAMP has been shown to be a mechanism by which Tregs induce immunosuppression. In fact, Tregs express high levels of cAMP, and are able to induce cAMP accumulation in activated target cells by multiple mechanisms [34,35]. Taking into consideration that GLP-1R activation modulates Treg function [15], it is possible to speculate that this mechanism is cAMP dependent.…”

Section: And 5)mentioning

confidence: 99%

Glucagon-like peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells

et al. 2010

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“…The Tax-inducible expression of connexin 43 (6), a major component of lymphocytic gap junctions with enhanced selectivity for cAMP (28), strengthens this argument. On the other hand, cAMP may be secreted, as CD4 ϩ lymphocytes can exert regulatory functions through the release of cAMP into the extracellular space (52). ATLL sera are known to suppress the production of IL-2 via unknown suppressive factors that are sensitive to acid treatment (49), which is also a feature of cAMP (30).…”

Section: Discussionmentioning

confidence: 99%

Elevated Cyclic AMP Levels in T Lymphocytes Transformed by Human T-Cell Lymphotropic Virus Type 1

Kress

Schneider

Pichler

et al. 2010

J Virol

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Human T-cell lymphotropic virus type 1 (HTLV-1), the cause of adult T-cell leukemia/lymphoma (ATLL), transforms CD4؉ T cells to permanent growth through its transactivator Tax. HTLV-1-transformed cells share phenotypic properties with memory and regulatory T cells (T-reg). Murine T-reg-mediated suppression employs elevated cyclic AMP (cAMP) levels as a key regulator. This led us to determine cAMP levels in HTLV-1-transformed cells. We found elevated cAMP concentrations as a consistent feature of all HTLV-1-transformed cell lines, including in vitro-HTLV-1-transformed, Tax-transformed, and patient-derived cells. In transformed cells with conditional Tax expression, high cAMP levels coincided with the presence of Tax but were lost without it. However, transient ectopic expression of Tax alone was not sufficient to induce cAMP. We found specific downregulation of the cAMP-degrading phosphodiesterase 3B (PDE3B) in HTLV-1-transformed cells, which was independent of Tax in transient expression experiments. This is in line with the notion that PDE3B transcripts and cAMP levels are inversely correlated. Overexpression of PDE3B led to a decrease of cAMP in HTLV-1-transformed cells. Decreased expression of PDE3B was associated with inhibitory histone modifications at the PDE3B promoter and the PDE3B locus. In summary, Tax transformation and its continuous expression contribute to elevated cAMP levels, which may be regulated through PDE3B suppression. This shows that HTLV-1-transformed cells assume biological features of long-lived T-cell populations that potentially contribute to viral persistence.

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Human CD4+ T lymphocytes with increased intracellular cAMP levels exert regulatory functions by releasing extracellular cAMP

Cited by 26 publications

References 46 publications

Cholera Toxin andEscherichia coliHeat-Labile Enterotoxin, but Not Their Nontoxic Counterparts, Improve the Antigen-Presenting Cell Function of Human B Lymphocytes

Cholera Toxin andEscherichia coliHeat-Labile Enterotoxin, but Not Their Nontoxic Counterparts, Improve the Antigen-Presenting Cell Function of Human B Lymphocytes

Glucagon-like peptide-1 receptor signalling selectively regulates murine lymphocyte proliferation and maintenance of peripheral regulatory T cells

Elevated Cyclic AMP Levels in T Lymphocytes Transformed by Human T-Cell Lymphotropic Virus Type 1

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