Cholera Toxin Directly Enhances IL-17A Production from Human CD4+ T Cells

Tsai, Hsing-Chuan; Wu, Reen

doi:10.4049/jimmunol.1301079

Cited by 15 publications

(16 citation statements)

References 51 publications

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“…Since the cytokines and the receptors involved in the production of IL-17A and IFN-γ share common components, it is important to know if distinctive T cell subsets expressing these cytokines exist in ruminants as they appear to in other mammalian species. We found that the major T cell subsets (CD4+ve and WC-1+ve) can express IL-17A (Figures 5 and 6), consistent with reports in humans [50] and mice [51, 52]. We found CD8+ve IL-17A for cattle PBMC but had insufficient cells to confirm their presence in PMA/ionomycin-stimulated ovine PBMC.…”

Section: Discussionsupporting

confidence: 89%

Enhancing the toolbox to study IL-17A in cattle and sheep

Wattegedera

Corripio-Miyar

Pang

et al. 2017

Vet Res

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The development of methods to detect cytokine expression by T cell subsets in ruminants is fundamental to strategic development of new livestock vaccines for prevention of infectious diseases. It has been possible to detect T cell expression of IFN-γ, IL-4 and IL-10 in ruminants for many years but methods to detect expression of IL-17A are relatively limited. To address this gap in capability we have cloned bovine and ovine IL-17A cDNAs and expressed biologically-active recombinant proteins in Chinese Hamster Ovary (CHO) cells. We used the transfected CHO cells to screen commercially-available antibodies for their ability to detect IL-17A expression intracellularly and in culture supernates. We demonstrate that an ELISA for bovine IL-17A detects native ovine IL-17A. Moreover, the constituent polyclonal antibodies (pabs) in the ELISA were used to enumerate peripheral blood mononuclear cells (PBMC) expressing IL-17A from cattle and sheep by ELISpot. We identified two monoclonal antibodies (mabs) that detect recombinant intracellular IL-17A in CHO cells by flow cytometry. One of these mabs was used to detect native intracellular IL-17A expression in PBMC in conjunction with cell surface phenotyping mabs [CD4+ve, CD8+ve and Workshop Cluster 1 (WC-1)+ve gamma-delta (γδ)] we show that distinct T cell subsets in cattle (defined as CD4+ve, CD8+ve or WC-1+ve) and sheep (defined as CD4+ve or WC-1+ve) can express IL-17A following activation. These novel techniques provide a solid basis to investigate IL-17A expression and define specific CD4+ve T cell subset activation in ruminants.Electronic supplementary materialThe online version of this article (doi:10.1186/s13567-017-0426-5) contains supplementary material, which is available to authorized users.

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Section: Discussionsupporting

confidence: 89%

Enhancing the toolbox to study IL-17A in cattle and sheep

Wattegedera

Corripio-Miyar

Pang

et al. 2017

Vet Res

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“…126–128 Specifically, T H 1 cells are more sensitive than T H 2 cells to inhibition by CT. 129,130 However, in our study, CT upregulated IL-17A production by human CD4 + T cells and also promoted T H 17-cell differentiation. 131 The addition of cAMP analogs mimicked the CT effect on IL-17A induction, thus suggesting the involvement of cAMP-signaling pathway in the regulation of IL-17A production. Utilizing different cAMP analogs and the promoter-reporter activity assay, we demonstrated that CT-induced IL-17A production occurs via a cAMP-PKA pathway.…”

Section: Mechanisms Of Ct-induced Th17 Responsesmentioning

confidence: 88%

Mechanisms of Cholera Toxin in the Modulation of TH17 Responses

Tsai

Wu²

2015

Crit Rev Immunol

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Numerous studies have shown that TH17 cells and their signature cytokine IL-17A are critical to host defense against various bacterial and fungal infections. The protective responses mediated by TH17 cells and IL-17A include the recruitment of neutrophils, release of antimicrobial peptides and chemokines, and enhanced tight junction of epithelial cells. Due to the importance of TH17 cells in infections, efforts have been made to develop TH17-based vaccines. The goal of vaccination is to establish a protective immunological memory. Most currently approved vaccines are antibody-based and have limited protection against stereotypically different strains. Studies show that T-cell–based vaccines may overcome this limitation and protect hosts against infection of different strains. Two main strategies are used to develop TH17 vaccines: identification of TH17-specific antigens and TH17-skewing adjuvants. Studies have revealed that cholera toxin (CT) induces a potent Th17 response following vaccination. Antigen vaccination along with CT induces a robust TH17 response, which is sometimes accompanied by TH1 responses. Due to the toxicity of CT, it is hard to apply CT in a clinical setting. Thus, understanding how CT modulates TH17 responses may lead to the development of successful TH17-based vaccines.

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“…In addition, in vitro HIV infection also dampens the T cells’ proliferative ability through elevated intracellular cAMP levels . In contrast to its immune suppression, our group and others found that CT and cAMP also induces Th17 responses by acting on dendritic cells or T cells . In this study, we demonstrate that CT induces IL‐17A expression by the activation of a cAMP/PKA/CREB cascade, then CREB trans ‐activating IL‐17A promoter by binding to the cis ‐regulatory element, CRE motif at −183, of the promoter.…”

Section: Discussionmentioning

confidence: 56%

“…The constructs were termed IL17p/WT (wild‐type), IL17p/CREmt1, IL17p/CREmt2 and IL17p/CREmt1/2. Primers used to create the mutations were described previously . CREB1‐specific small interfering RNA (siRNA) non‐targeted oligomer controls were purchased from Life Technologies (Carlsbad, CA).…”

Section: Methodsmentioning

confidence: 99%

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Cholera toxin enhances interleukin‐17A production in both CD4⁺ and CD8⁺ cells via a cAMP/protein kinase A‐mediated interleukin‐17A promoter activation

et al. 2018

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Cholera toxin (CT) is a bacterial component that increases intracellular cAMP levels in host cells and suppresses T-cell activation. Recently, CT was reported to induce T helper type 17-skewing dendritic cells and activate interleukin-17A (IL-17A) production in CD4 T cells through a cAMP-dependent pathway. However, the underlying mechanism by which cAMP regulates IL-17A production in T cells is not completely defined. In this study, we took advantage of a small molecule protein kinase A (PKA) inhibitor (H89) and different cAMP analogues: a PKA-specific activator (N6-benzoyl-adenosine-cAMP), an exchange protein activated by cAMP-specific activator (Rp-8-chlorophenylthio-2'-O-methyl cAMP), and a PKA inhibitor (Rp-8-bromo-cAMP), to elucidate the signalling cascade of cAMP in IL-17A regulation in T cells. We found that CT induced IL-17A production and IL-17A promoter activity in activated CD4 T cells through a cAMP/PKA pathway. Moreover, this regulation was via cAMP-response element binding protein (CREB) -mediated transcriptional activation by using the transfection of an IL-17A promoter-luciferase reporter construct and CREB small interfering RNA in Jurkat cells. Also, we showed that CREB bound to the CRE motif located at -183 of the IL-17A promoter in vitro. Most interestingly, not only in CD4 T cells, CT also enhanced cAMP/PKA-dependent IL-17A production and CREB phosphorylation in CD8 T cells. In conclusion, our data suggest that CT induces an IL-17A-dominated immune microenvironment through the cAMP/PKA/CREB signalling pathway. Our study also highlights the potentials of CT and cAMP in modulating T helper type 17 responses in vivo.

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Cholera Toxin Directly Enhances IL-17A Production from Human CD4+ T Cells

Cited by 15 publications

References 51 publications

Enhancing the toolbox to study IL-17A in cattle and sheep

Enhancing the toolbox to study IL-17A in cattle and sheep

Mechanisms of Cholera Toxin in the Modulation of TH17 Responses

Cholera toxin enhances interleukin‐17A production in both CD4⁺ and CD8⁺ cells via a cAMP/protein kinase A‐mediated interleukin‐17A promoter activation

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Cholera Toxin Directly Enhances IL-17A Production from Human CD4+ T Cells

Cited by 15 publications

References 51 publications

Enhancing the toolbox to study IL-17A in cattle and sheep

Enhancing the toolbox to study IL-17A in cattle and sheep

Mechanisms of Cholera Toxin in the Modulation of TH17 Responses

Cholera toxin enhances interleukin‐17A production in both CD4+ and CD8+ cells via a cAMP/protein kinase A‐mediated interleukin‐17A promoter activation

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Cholera toxin enhances interleukin‐17A production in both CD4⁺ and CD8⁺ cells via a cAMP/protein kinase A‐mediated interleukin‐17A promoter activation