Protein kinase Cδ is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria

Fukao, Saori; Haniuda, Kei; Tamaki, Hiromasa; Kitamura, Daisuke

doi:10.7554/elife.72116

Cited by 5 publications

(1 citation statement)

References 64 publications

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“…This humoral regulation was due to the release of VIP from sensory neurons and the resulting stimulation of plasma cells via the VIP1 receptor. We demonstrate that B-cells have VIP1 receptors, which stimulate PKCs that are critical to the development and release of immunoglobulins 64,65 .…”

Section: Discussionmentioning

confidence: 82%

Sensory neurons regulate stimulus-dependent humoral immunity

Aguilar,

Zhu,

Millet

et al. 2024

Preprint

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Sensory neurons sense pathogenic infiltration, serving to inform immune coordination of host defense. However, sensory neuron-immune interactions have been predominantly shown to drive innate immune responses. Humoral memory, whether protective or destructive, is acquired early in life - as demonstrated by both early exposure to streptococci and allergic disease onset. Our study further defines the role of sensory neuron influence on humoral immunity in the lung. Using a murine model of Streptococcus pneumonia pre-exposure and infection and a model of allergic asthma, we show that sensory neurons are required for B-cell and plasma cell recruitment and antibody production. In response to S. pneumoniae, sensory neuron depletion resulted in a larger bacterial burden, reduced B-cell populations, IgG release and neutrophil stimulation. Conversely, sensory neuron depletion reduced B-cell populations, IgE and asthmatic characteristics during allergen-induced airway inflammation. The sensory neuron neuropeptide released within each model differed. With bacterial infection, vasoactive intestinal polypeptide (VIP) was preferentially released, whereas substance P was released in response to asthma. Administration of VIP into sensory neuron-depleted mice suppressed bacterial burden and increased IgG levels, while VIP1R deficiency increased susceptibility to bacterial infection. Sensory neuron-depleted mice treated with substance P increased IgE and asthma, while substance P genetic ablation resulted in blunted IgE, similar to sensory neuron-depleted asthmatic mice. These data demonstrate that the immunogen differentially stimulates sensory neurons to release specific neuropeptides which specifically target B-cells. Targeting sensory neurons may provide an alternate treatment pathway for diseases involved with insufficient and/or aggravated humoral immunity.

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Section: Discussionmentioning

confidence: 82%

Sensory neurons regulate stimulus-dependent humoral immunity

Aguilar,

Zhu,

Millet

et al. 2024

Preprint

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Phenotypic Variability in PRKCD: a Review of the Literature

Jefferson,

Ramanan,

Jolles

et al. 2023

J Clin Immunol

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B cell-intrinsic DNase1L3 is essential for the T cell-independent type II response in mice

Kato

Haniuda

Fukao

et al. 2023

International Immunology

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T-cell independent type II (TI-II) antigens, such as capsular polysaccharides, have multivalent epitope, which induce B cell activation, plasma cell differentiation and antibody production by strongly cross-linking B-cell receptors. However, the mechanism of B cell activation by TI-II antigens remains unclear. In this study, we demonstrate that DNA endonuclease DNase1L3 (also termed DNase γ) is required for the TI-II response. The production of antigen-specific antibodies was severely diminished in DNase1L3-deficient mice upon immunization with TI-II antigens, but not with TD antigens. Bone-marrow chimeric mice and B cell transfer experiments revealed that B-cell-intrinsic DNase1L3 was required for the TI-II response. DNase1L3-deficient B cells were defective in cell proliferation and plasma cell differentiation in the TI-II response in vivo as well as in vitro, which was not rescued by co-culture with DNase1L3-sufficient B cells in vitro, disproving an involvement of a secretory DNase1L3. In vitro stimulation with TI-II antigen transiently increased expression of DNase1L3 and its translocation into the nucleus. RNA-seq analysis of ex vivo B cells having been responded to TI-II antigen in vivo revealed a marked reduction of Myc-target gene sets in DNase1L3-deficient B cells. Expression of IRF4, the gene of which Myc targets, was diminished in the ex vivo DNase1L3-deficient B cells, in which forced expression of IRF4 restored the TI-II response in vivo. These data revealed an unexpected role of DNase1L3 in a missing link between B-cell receptor signaling and B cell activation in the TI-II response, giving a valuable clue to molecularly dissect this response.

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Protein kinase Cδ is essential for the IgG response against T-cell-independent type 2 antigens and commensal bacteria

Cited by 5 publications

References 64 publications

Sensory neurons regulate stimulus-dependent humoral immunity

Sensory neurons regulate stimulus-dependent humoral immunity

Phenotypic Variability in PRKCD: a Review of the Literature

B cell-intrinsic DNase1L3 is essential for the T cell-independent type II response in mice

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