1. Immunology and Inflammation
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Inflammasome activation leads to cDC1-independent cross-priming of CD8 T cells by epithelial cell derived antigen

  1. Katherine A Deets
  2. Randilea Nichols Doyle
  3. Isabella Rauch
  4. Russell E Vance  Is a corresponding author
  1. University of California, Berkeley, United States
  2. Oregon Health and Science University, United States
Research Article
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Cite this article as: eLife 2021;10:e72082 doi: 10.7554/eLife.72082

Abstract

The innate immune system detects pathogens and initiates adaptive immune responses. Inflammasomes are central components of the innate immune system, but whether inflammasomes provide sufficient signals to activate adaptive immunity is unclear. In intestinal epithelial cells (IECs), inflammasomes activate a lytic form of cell death called pyroptosis, leading to epithelial cell expulsion and the release of cytokines. Here we employed a genetic system to show that simultaneous antigen expression and inflammasome activation specifically in IECs is sufficient to activate CD8+ T cells. By genetic elimination of direct T cell priming by IECs, we found that IEC-derived antigens are cross-presented to CD8+ T cells. However, cross-presentation of IEC-derived antigen to CD8+ T cells only partially depended on IEC pyroptosis. In the absence of inflammasome activation, cross-priming of CD8+ T cells required Batf3+ dendritic cells (cDC1), whereas cross-priming in the presence of pyroptosis required a Zbtb26+ but Batf3-independent cDC population. These data suggest the existence of parallel pyroptosis-dependent and pyroptosis-independent pathways for cross-presentation of IEC-derived antigens.

Data availability

Immunofluorescence images have been deposited in Dryad and can be found at https://doi.org/10.6078/D1ST46. All remaining data generated or analyzed during this study are included in the manuscript and supporting files; Source Data files have been provided for Figures 1-6, Figure 3-figure supplement 1, Figure 4-figure supplement 1, Figure 5-figure supplement 1, Figure 5-figure supplement 4, Figure 6-figure supplement 2.

The following data sets were generated

Article and author information

Author details

  1. Katherine A Deets

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  2. Randilea Nichols Doyle

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  3. Isabella Rauch

    Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, United States
    Competing interests
    No competing interests declared.
  4. Russell E Vance

    Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States
    For correspondence
    rvance@berkeley.edu
    Competing interests
    Russell E Vance, consults for Ventus Therapeutics and Tempest Therapeutics and is a Reviewing Editor for eLife..
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-6686-3912

Funding

National Institutes of Health (AI075039)

  • Russell E Vance

National Institutes of Health (AI063302)

  • Russell E Vance

National Institutes of Health (AI155634)

  • Russell E Vance

Howard Hughes Medical Institute (Investigator Award)

  • Russell E Vance

National Institutes of Health (5T32GM007232)

  • Katherine A Deets

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

Ethics

Animal experimentation: This study was performed in strict accordance with the recommendations in the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. Animal studies were approved by the UC Berkeley Animal Care and Use Committee (current protocol number: AUP-2014-09-6665-2).

Reviewing Editor

  1. Chyung-Ru Wang, Northwestern University, United States

Publication history

  1. Preprint posted: July 8, 2021 (view preprint)
  2. Received: July 9, 2021
  3. Accepted: December 21, 2021
  4. Accepted Manuscript published: December 23, 2021 (version 1)
  5. Version of Record published: December 31, 2021 (version 2)

Copyright

© 2021, Deets 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.

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