Mucosal adjuvant activity of cholera toxin requires Th17 cells and protects against inhalation anthrax

Datta, Sandip K.; Sabet, Mojgan; Nguyen, Kim; Valdez, Patricia; González‐Navajas, José M.; Islam, Shamima; Mihajlov, Ivan; Fierer, Joshua; Insel, Paul A.; Webster, Nicholas J. G.; Guiney, Donald G.; Raz, Eyal

doi:10.1073/pnas.1002348107

Cited by 144 publications

(143 citation statements)

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“…4). These data, combined with our previous observations that show induction of Th17 response (16) by high levels of cAMP in DC mostly via Gαs activation, indicate that in addition to PRR, signaling via regulators of cAMP levels, Gαs, and Gαi in CD11c + DC (and not in CD11c − ILC2 cells) (38) contributes to Th subset differentiation. Furthermore, the current findings help explain certain previous data, for example evidence that CGRP, a neuronally derived peptide that binds to a Gs-coupled receptor, can be an antiinflammatory mediator in the setting of allergic airway inflammation (39).…”

Section: Discussionsupporting

confidence: 77%

“…Based on these findings and our previous work that identified a role for cAMP in DC in Th17 induction (16), we hypothesized that cAMP regulates DC and affects Th differentiation bias. To test this hypothesis, we studied the regulation of DC activity by heterotrimeric (αβγ) GTP binding proteins that regulate cAMP synthesis through their modulation of the activity of adenylyl cyclases (ACs): Gαs, which stimulates AC activity, and Gαi, which inhibits membrane AC activity.…”

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confidence: 66%

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Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

Lee¹,

Kim

Murray

et al. 2015

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

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The inductive role of dendritic cells (DC) in Th2 differentiation has not been fully defined. We addressed this gap in knowledge by focusing on signaling events mediated by the heterotrimeric GTP binding proteins Gαs, and Gαi, which respectively stimulate and inhibit the activation of adenylyl cyclases and the synthesis of cAMP. We show here that deletion of Gnas, the gene that encodes Gαs in mouse CD11c + cells (Gnas ΔCD11c mice), and the accompanying decrease in cAMP provoke Th2 polarization and yields a prominent allergic phenotype, whereas increases in cAMP inhibit these responses. The effects of cAMP on DC can be demonstrated in vitro and in vivo and are mediated via PKA. Certain gene products made by Gnas ΔCD11c DC affect the Th2 bias. These findings imply that G protein-coupled receptors, the physiological regulators of Gαs and Gαi activation and cAMP formation, act via PKA to regulate Th bias in DC and in turn, Th2-mediated immunopathologies.cAMP | dendritic cells | Th2 | PKA | asthma

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Section: Discussionsupporting

confidence: 77%

mentioning

confidence: 66%

Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

Lee¹,

Kim

Murray

et al. 2015

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

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“…Several other bacteria-derived OMV-based antigens are also in development, while an OMV-based vaccine against Nesseria meningitidis has been licensed for (injectable) use in humans [107]. Anthrax spores have also been evaluated by the nasal route and successfully protected against challenge following vaccination [108]. The potential of these systems for oral vaccination is less clear but their efficacy could be enhanced by capsule based approaches with incorporated adjuvants.…”

Section: Classes Of Mucosal Antigenmentioning

confidence: 99%

Delivery strategies to enhance oral vaccination against enteric infections

Davitt

Lavelle

2015

Advanced Drug Delivery Reviews

131

102

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Section: Introductionmentioning

confidence: 99%

“…This dominance of IL-17 was also observed in response to the CT b subunit (CTB). Although the precise mechanism for the adjuvant effect of CT is not completely understood, it appears that CTB targets DCs in vivo by binding to the cell membrane ganglioside GM1 [20]; moreover, the CT a subunit (CTA) triggers the PKA-mediated induction of cAMP, which plays a critical role in the subsequent induction of Th17 [21].Following skin immunization, both migrating and LN resident cells can cooperate in T-cell priming [22], and the delayed-type hypersensitivity (DTH) response seems to be dependent on migrating cells [23]; however, the dominant CD4 1 T-cell immune response that is elicited after cutaneous immunization and the role of migrating DCs in the presence of adjuvants needs to be further evaluated. Here, we used intradermal (i.d.)…”

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confidence: 99%

Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

et al. 2011

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The nature of CD4 1 T-cell responses after skin immunization and the role of migrating DCs in the presence of adjuvants in the elicited response are interesting issues to be investigated. Here, we evaluated the priming of CD4 1 T cells following ear immunization with low doses of model antigens in combination with either cholera toxin (CT) or the non-toxic b CT subunit (CTB) as an adjuvant. Following immunization with CT, we found efficient antigen presentation that is reflected in the production of IFN-c and IL-17 by CD4 1 T cells over IL-4 or IL-5 production. The CTB-induced activation of DCs in the ear occurred without visible inflammation, which reflects a similar type of CD4 1 T-cell differentiation. In both cases, the elicited response was dependent on the presence of migrating skin cells. Remarkably, immunization with CT or with CTB led to the induction of a delayed-type hypersensitivity (DTH) response in the ear. The DTH response that was induced by CT immunization was dependent on IL-17 and partially dependent on IFN-c activity. These results indicate that both CT and CTB induce an efficient CD4 1 T-cell response to a co-administered antigen following ear immunization that is dependent on migrating DCs.Key words: DCs . Migrating DCs . Skin immunization Supporting Information available online IntroductionThe skin is the first line of defense against microbial pathogens. There is supporting evidence that DCs are crucial for the initiation, polarization and control of the adaptive immune response [1,2]. Efficient immunosurveillance in the skin is based upon the continuous traffic of cells from the skin to the draining lymph nodes. Although Langerhans cells (LCs) have been shown to be potent APCs in vitro [3], in vivo approaches have produced conflicting data regarding their role in T-cell priming [4,5]. Dermal DCs are also migrating DCs that colonize lymph nodes more rapidly than LCs [6,7], and different roles for skin DC subsets in T-cell priming have been reported [7][8][9]. Skin immunization has yielded controversial data, with some reports supporting a Th2-type response [10,11] and others a Th1-type response [12,13]. IL-17-producing CD4 1 T cells (Th17) have also been found after skin immunization [13,14]. 2894Cholera toxin (CT) has a strong adjuvant effect [15]. When administered in the mucosa, CT can elicit a Th2-type response that is based on the production of IL-4, IL-5 and IL-10 but virtually no 17]. However, a mixed Th1/Th2 response that produces both IFN-g and IL-4 has also been observed [18], and the administration of ovalbumin (OVA) in combination with CT elicits a dominant Th17 response following intranasal immunization [19]. This dominance of IL-17 was also observed in response to the CT b subunit (CTB). Although the precise mechanism for the adjuvant effect of CT is not completely understood, it appears that CTB targets DCs in vivo by binding to the cell membrane ganglioside GM1 [20]; moreover, the CT a subunit (CTA) triggers the PKA-mediated induction of cAMP, which plays a critical role ...

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Mucosal adjuvant activity of cholera toxin requires Th17 cells and protects against inhalation anthrax

Cited by 144 publications

References 46 publications

Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

Cyclic AMP concentrations in dendritic cells induce and regulate Th2 immunity and allergic asthma

Delivery strategies to enhance oral vaccination against enteric infections

Intradermal immunization in the ear with cholera toxin and its non‐toxic β subunit promotes efficient Th1 and Th17 differentiation dependent on migrating DCs

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