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IgE-activated mast cells enhance TLR4-mediated antigen-specific CD4⁺ T cell responses.

ABSTRACT: Mast cells are potent mediators of allergy and asthma, yet their role in regulating adaptive immunity remains ambiguous. On the surface of mast cells, the crosslinking of IgE bound to FcεRI by a specific antigen recognized by that IgE triggers the release of immune mediators such as histamine and cytokines capable of activating other immune cells; however, little is known about the mast cell contribution to the induction of endogenous, antigen-specific CD4⁺ T cells. Here we examined the effects of specific mast cell activation in vivo on the initiation of an antigen-specific CD4⁺ T cell response. While CD4⁺ T cells were not enhanced by FcεRI stimulation alone, their activation was synergistically enhanced when FcεRI activation was combined with TLR4 stimulation. This enhanced activation was dependent on global TLR4 stimulation but appeared to be less dependent on mast cell expressed TLR4. This study provides important new evidence to support the role of mast cells as mediators of the antigen-specific adaptive immune response.

SUBMITTER: Phong BL

PROVIDER: S-EPMC8102524 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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IgE-activated mast cells enhance TLR4-mediated antigen-specific CD4<sup>+</sup> T cell responses.

Phong Binh L BL D'Souza Shaina J SJ Baudier Robin L RL Wu Eric E Immethun Victoria E VE Bauer David L DL McLachlan James B JB

Scientific reports 20210506 1

Mast cells are potent mediators of allergy and asthma, yet their role in regulating adaptive immunity remains ambiguous. On the surface of mast cells, the crosslinking of IgE bound to FcεRI by a specific antigen recognized by that IgE triggers the release of immune mediators such as histamine and cytokines capable of activating other immune cells; however, little is known about the mast cell contribution to the induction of endogenous, antigen-specific CD4<sup>+</sup> T cells. Here we examined t ...[more]

PMID: 33958642

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Project description:BackgroundEfficient development of atopic diseases requires interactions between allergen and adjuvant to initiate and amplify the underlying inflammatory responses. Substance P (SP) and hemokinin-1 (HK-1) are neuropeptides that signal through the neurokinin-1 receptor (NK1R) to promote inflammation. Mast cells initiate the symptoms and tissue effects of atopic disorders, secreting TNF and IL-6 after FcεRI cross-linking by antigen-IgE complexes (FcεRI-activated mast cells [FcεRI-MCs]). Additionally, MCs express the NK1R, suggesting an adjuvant role for NK1R agonists in FcεRI-MC-mediated pathologies; however, in-depth research addressing this relevant aspect of MC biology is lacking.ObjectiveWe sought to investigate the effect of NK1R signaling and the individual roles of SP and HK-1 as potential adjuvants for FcεRI-MC-mediated allergic disorders.MethodsBone marrow-derived mast cells (BMMCs) from C57BL/6 wild-type (WT) or NK1R(-/-) mice were used to investigate the effects of NK1R signaling on FcεRI-MCs. BMMCs generated from Tac1(-/-) mice or after culture with Tac4 small interfering RNA were used to address the adjuvancy of SP and HK-1. WT, NK1R(-/-), and c-Kit(W-sh/W-sh) mice reconstituted with WT or NK1R(-/-) BMMCs were used to evaluate NK1R signaling on FcεRI-MC-mediated passive local and systemic anaphylaxis and on airway inflammation.ResultsFcεRI-activated MCs upregulated NK1R and HK-1 transcripts and protein synthesis, without modifying SP expression. In a positive signaling loop HK-1 promoted TNF and IL-6 secretion by MC degranulation and protein synthesis, the latter through the phosphoinositide 3-kinase/Akt/nuclear factor κB pathways. In vivo NK1R signaling was necessary for the development of passive local and systemic anaphylaxis and airway inflammation.ConclusionsFcεRI stimulation of MCs promotes autocrine secretion of HK-1, which signals through NK1R to provide adjuvancy for efficient development of FcεRI-MC-mediated disorders.

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IgE-activated mast cells enhance TLR4-mediated antigen-specific CD4⁺ T cell responses.

Publications

IgE-activated mast cells enhance TLR4-mediated antigen-specific CD4<sup>+</sup> T cell responses.

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IgE-activated mast cells enhance TLR4-mediated antigen-specific CD4+ T cell responses.

Publications

IgE-activated mast cells enhance TLR4-mediated antigen-specific CD4<sup>+</sup> T cell responses.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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IgE-activated mast cells enhance TLR4-mediated antigen-specific CD4⁺ T cell responses.