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

  1. Saori Fukao
  2. Kei Haniuda
  3. Hiromasa Tamaki
  4. Daisuke Kitamura  Is a corresponding author
  1. Research Institute for Biomedical Sciences, Tokyo University of Science, Japan

Abstract

Antigens (Ags) with multivalent and repetitive structure elicit IgG production in a T cell-independent manner. However, the mechanisms by which such T cell-independent type-2 (TI-2) Ags induce IgG responses remain obscure. Here we report that BCR engagement with a TI-2 Ag but not with a T cell-dependent (TD) Ag was able to induce the transcription of Aicda encoding activation-induced cytidine deaminase (AID) and efficient class switching to IgG3 upon co-stimulation with IL-1 or IFN-α in mouse B cells. TI-2 Ags strongly induced the phosphorylation of protein kinase C (PKC)δ and PKCδ mediated the Aicda transcription through the induction of BATF, the key transcriptional regulator of Aicda. In PKCδ-deficient mice, production of IgG was intact against TD Ag but abrogated against typical TI-2 Ags as well as commensal bacteria, and experimental disruption of the gut epithelial barrier resulted in fatal bacteremia. Thus, our results have revealed novel molecular requirements for class-switching in the TI-2 response and highlighted its importance in homeostatic commensal-specific IgG production.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided for Figures 1-6, and figure supplements for Figures 1-3 and 5.

Article and author information

Author details

  1. Saori Fukao

    Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan
    Competing interests
    The authors declare that no competing interests exist.
  2. Kei Haniuda

    Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan
    Competing interests
    The authors declare that no competing interests exist.
  3. Hiromasa Tamaki

    Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan
    Competing interests
    The authors declare that no competing interests exist.
  4. Daisuke Kitamura

    Research Institute for Biomedical Sciences, Tokyo University of Science, Noda, Japan
    For correspondence
    kitamura@rs.tus.ac.jp
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-5195-0474

Funding

Japan Society for the Promotion of Science (Grant-in-Aid for Early-Career Scientists,19K16700)

  • Saori Fukao

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice were maintained in the Tokyo University of Science (TUS) mouse facility under specific pathogen-free conditions. Mouse procedures were performed under protocols approved by the TUS Animal Care and Use Committee (Approval No.: S19017, S20011).

Copyright

© 2021, Fukao et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 880
    views
  • 169
    downloads
  • 5
    citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Saori Fukao
  2. Kei Haniuda
  3. Hiromasa Tamaki
  4. Daisuke Kitamura
(2021)
Protein kinase Cδ is essential for the IgG response against T cell-independent type 2 antigens and commensal bacteria
eLife 10:e72116.
https://doi.org/10.7554/eLife.72116

Share this article

https://doi.org/10.7554/eLife.72116

Further reading

    1. Immunology and Inflammation
    Alexandra a Aybar-Torres, Lennon A Saldarriaga ... Lei Jin
    Research Article

    The significance of STING1 gene in tissue inflammation and cancer immunotherapy has been increasingly recognized. Intriguingly, common human STING1 alleles R71H-G230A-R293Q (HAQ) and G230A-R293Q (AQ) are carried by ~60% of East Asians and ~40% of Africans, respectively. Here, we examine the modulatory effects of HAQ, AQ alleles on STING-associated vasculopathy with onset in infancy (SAVI), an autosomal dominant, fatal inflammatory disease caused by gain-of-function human STING1 mutations. CD4 T cellpenia is evident in SAVI patients and mouse models. Using Sting1 knock-in mice expressing common human STING1 alleles HAQ, AQ, and Q293, we found that HAQ, AQ, and Q293 splenocytes resist STING1-mediated cell death ex vivo, establishing a critical role of STING1 residue 293 in cell death. The HAQ/SAVI(N153S) and AQ/SAVI(N153S) mice did not have CD4 T cellpenia. The HAQ/SAVI(N153S), AQ/SAVI(N153S) mice have more (~10-fold, ~20-fold, respectively) T-regs than WT/SAVI(N153S) mice. Remarkably, while they have comparable TBK1, IRF3, and NFκB activation as the WT/SAVI, the AQ/SAVI mice have no tissue inflammation, regular body weight, and normal lifespan. We propose that STING1 activation promotes tissue inflammation by depleting T-regs cells in vivo. Billions of modern humans have the dominant HAQ, AQ alleles. STING1 research and STING1-targeting immunotherapy should consider STING1 heterogeneity in humans.

    1. Immunology and Inflammation
    Arijit Chakraborty, Arunava Bandyopadhaya ... Laurence G Rahme
    Research Article

    How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2’-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in murine macrophages’ mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from decreased pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (Mpc1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (Esrra). Consequently, Esrra exhibits weakened binding to the Mpc1 promoter. This outcome arises from the impaired interaction between Esrra and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (Ppargc1a). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and, consequently reduced ATP production in tolerized murine and human macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of Mpc1 and Esrra and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedented mechanism of host tolerance to infection involving the Ppargc1a/Esrra axis in its influence on Mpc1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings pave the way for developing treatments to bolster host resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.