Critical role of mammalian target of rapamycin for IL-10 dendritic cell induction by a flagellin A conjugate in preventing allergic sensitization

Schülke, Stefan; Fiedler, Anna H.; Junker, Ann Christine; Flaczyk, Adam; Wolfheimer, Sonja; Wangorsch, Andrea; Heinz, A.; Beckert, Hendrik; Nagl, Birgit; Bohle, Barbara; Vieths, Stefan; Toda, Masako; Scheurer, Stephan

doi:10.1016/j.jaci.2017.07.002

Cited by 27 publications

(92 citation statements)

References 45 publications

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“…Overall, our data point against the use of alum in order to preserve the tolerogenic properties imprinted by allergoids conjugated to mannan in DCs. This should be also taken into account when considering novel vaccination approaches aimed to induce tolerogenic DCs, especially when the mTOR pathway is involved in such effects . This might be also relevance for those vaccines based on triggering trained immunity, in which the Akt/mTOR activation is essential …”

Section: Discussionmentioning

confidence: 99%

“…Schülke et al also described that in mDCs activated by the fusion protein rFlaA:Betv1, mTOR regulates IL-10 production. 28 Similarly, the expression of PD-L1, a key molecule for the induction of functional FOXP3 + Treg cells, 36,46,47 has been shown to be regulated by mTOR in DCs. 48 Herein, we show that the inhibition of PM-induced mTOR signalling and the reduction in PD-L1 expression in DCs by alum correlate with a reduction on the generation of FOXP3 + Treg cells.…”

Section: Discussionmentioning

confidence: 99%

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Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Benito-Villalvilla

Soria

Pérez‐Diego

et al. 2019

Allergy

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Background Polymerized allergoids conjugated to mannan (PM) are suitable vaccines for allergen‐specific immunotherapy (AIT). Alum remains the most widely used adjuvant in AIT, but its way of action is not completely elucidated. The better understanding of the mechanisms underlying alum adjuvanticity could help to improve AIT vaccine formulations. Objective We sought to investigate the potential influence of alum in the tolerogenic properties imprinted by PM at the molecular level. Methods Flow cytometry, ELISAs, cocultures, intracellular staining and suppression assays were performed to assess alum and PM effects in human dendritic cells (DCs). BALB/c mice were immunized with PM alone or adsorbed to alum. Allergen‐specific antibodies, splenocyte cytokine production and splenic forkhead box P3 (FOXP3)+ regulatory T (Treg) cells were quantified. Metabolic and immune pathways were also studied in human DCs. Results Alum decreases PD‐L1 expression and IL‐10 production induced by PM in human DCs and increases pro‐inflammatory cytokine production. Alum impairs PM‐induced functional FOXP3+ Treg cells and promotes Th1/Th2/Th17 responses. Subcutaneous immunization of mice with PM plus alum inhibits in vivo induction of Treg cells promoted by PM without altering the capacity to induce functional allergen‐specific blocking antibodies. Alum inhibits mTOR activation and alters metabolic reprogramming by shifting glycolytic pathways and inhibiting reactive oxygen species (ROS) production in PM‐activated DCs, impairing their capacity to generate functional Treg cells. Conclusion We uncover novel mechanisms by which alum impairs the tolerogenic properties induced by PM, which might well contribute to improve the formulation of novel vaccines for AIT.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Benito-Villalvilla

Soria

Pérez‐Diego

et al. 2019

Allergy

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“…In our own studies, we evaluated the induction of IL-10-producing mDCs using fusion proteins consisting of the recombinant TLR5-ligand flagellin A (rFlaA) from L. monocytogenes and either OVA from hen’s egg as a model allergen (rFlaA:OVA) ( 92 – 94 ), the major mugwort allergen Artemisia vulgaris allergen 1 (Art v1) (rFlaA:Artv1) ( 95 ), or the major birch pollen allergen Betula verrucosa allergen 1 (Bet v 1) (rFlaA:Betv1) ( 96 ). Such fusion proteins efficiently target TLR5 + immune cells, e.g., DCs, macrophages, and epithelial cells which take up, process, and present the fused antigen in the context of the flagellin-mediated cell activation.…”

Section: Strategies To Induce Dc-derived Il-10 Secretionmentioning

confidence: 99%

“…Mouse bone marrow-derived mDCs stimulated with such fusion proteins were strongly activated [upregulation of CD40, CD69, CD80, CD86, programmed cell death 1 ligand 2 (B7-DC, CD273), PD-L1], displayed highly increased levels of the target receptor TLR5 on their cell surface, and secreted both pro- (IL-1β, IL-6) and anti-inflammatory (IL-10) cytokines (Figure 3 A) ( 93 , 95 , 96 ). Interestingly, the non-fused mixture of both components (flagellin and allergen) did not have a comparable effect ( 93 , 95 , 96 ).…”

Section: Strategies To Induce Dc-derived Il-10 Secretionmentioning

confidence: 99%

Induction of Interleukin-10 Producing Dendritic Cells As a Tool to Suppress Allergen-Specific T Helper 2 Responses

2018

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Dendritic cells (DCs) are gatekeepers of the immune system that control induction and polarization of primary, antigen-specific immune responses. Depending on their maturation/activation status, the molecules expressed on their surface, and the cytokines produced DCs have been shown to either elicit immune responses through activation of effector T cells or induce tolerance through induction of either T cell anergy, regulatory T cells, or production of regulatory cytokines. Among the cytokines produced by tolerogenic DCs, interleukin 10 (IL-10) is a key regulatory cytokine limiting und ultimately terminating excessive T-cell responses to microbial pathogens to prevent chronic inflammation and tissue damage. Because of their important role in preventing autoimmune diseases, transplant rejection, allergic reactions, or in controlling chronic inflammation DCs have become an interesting tool to modulate antigen-specific immune responses. For the treatment of allergic inflammation, the aim is to downregulate allergen-specific T helper 2 (Th2) responses and the associated clinical symptoms [allergen-driven Th2 activation, Th2-driven immunoglobulin E (IgE) production, IgE-mediated mast cell and basophil activation, allergic inflammation]. Here, combining the presentation of allergens by DCs with a pro-tolerogenic, IL-10-producing phenotype is of special interest to modulate allergen-specific immune responses in the treatment of allergic diseases. This review discusses the reported strategies to induce DC-derived IL-10 secretion for the suppression of allergen-specific Th2-responses with a focus on IL-10 treatment, IL-10 transduction, and the usage of both whole bacteria and bacteria-derived components. Interestingly, while IL-10-producing DCs induced either by IL-10 treatment or IL-10 transduction are arrested in an immature/semi-mature state, treatment of DCs with live or killed bacteria as well as isolated bacterial components results in the induction of both anti-inflammatory IL-10 and pro-inflammatory, Th1-promoting IL-12 secretion often paralleled by an enhanced expression of co-stimulatory molecules on the stimulated DCs. By the secretion of DC-derived exosomes or CC-chemokine ligand 18, as well as the expression of inhibitory molecules like cytotoxic T lymphocyte-associated antigen 4, TNF receptor superfamily member 4, Ig-like transcript-22/cluster of differentiation 85, or programmed death-1, IL-10-producing DCs have been repeatedly shown to suppress antigen-specific Th2-responses. Therefore, DC-based vaccination approaches hold great potential to improve the treatment of allergic diseases.

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“…In an experimental Bet v 1 sensitization model, mice were vaccinated with a flagellin-allergen fusion protein (rFlaA:Bet v 1) containing the Toll-like receptor (TLR) 5 ligand flagellin A from Listeria monocytogenes and the birch pollen allergen Bet v 1. 37 Vaccination suppressed T H 2 responses from CD4 1 T cells and prevented allergic sensitization. In addition, rFlaA:Bet v 1 activated the mammalian target of rapamycin, with a subsequent increase in the metabolic activity of stimulated myeloid DCs.…”

Section: Dcsmentioning

confidence: 99%

Advances in mechanisms of allergic disease in 2017

Skevaki

Renz

2018

Journal of Allergy and Clinical Immunology

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This review highlights advances in mechanisms of allergic disease, particularly type 2 innate lymphoid cells, T H 2 lymphocytes, B cells, dendritic cells, microbiome and barrier function, eosinophils, and mast cells. During the last year, considerable progress has been made in the further characterization of type 2 inflammation controlled by both adaptive (T H 2) and type 2 innate lymphoid effector cells. New pathways of lymphocyte activation, trafficking, and recruitment and effector cell mechanisms have been discovered. The plasticity of lymphocyte effector cell responses is another area in which major progress has been achieved. Accumulating evidence will influence both our understanding of allergic disease and our efforts for allergy prevention and treatment.

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Critical role of mammalian target of rapamycin for IL-10 dendritic cell induction by a flagellin A conjugate in preventing allergic sensitization

Abstract: These results provide evidence that mammalian target of rapamycin is a key player involved in prevention of T2 responses by flagellin A conjugate vaccines.

Cited by 27 publications

References 45 publications

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Alum impairs tolerogenic properties induced by allergoid‐mannan conjugates inhibiting mTOR and metabolic reprogramming in human DCs

Induction of Interleukin-10 Producing Dendritic Cells As a Tool to Suppress Allergen-Specific T Helper 2 Responses

Advances in mechanisms of allergic disease in 2017

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