1. Cell Biology
  2. Immunology and Inflammation
Download icon

Mouse T cell priming is enhanced by maturation-dependent stiffening of the dendritic cell cortex

  1. Daniel Blumenthal  Is a corresponding author
  2. Vidhi Chandra
  3. Lyndsay Avery
  4. Janis K Burkhardt  Is a corresponding author
  1. The Children's Hospital of Philadelphia Research Institute, United States
  2. Children's Hospital of Philadelphia Research Institute, United States
Research Article
  • Cited 0
  • Views 470
  • Annotations
Cite this article as: eLife 2020;9:e55995 doi: 10.7554/eLife.55995

Abstract

T cell activation by dendritic cells (DCs) involves forces exerted by the T cell actin cytoskeleton, which are opposed by the cortical cytoskeleton of the interacting APC. During an immune response, DCs undergo a maturation process that optimizes their ability to efficiently prime naïve T cells. Using atomic force microscopy, we find that during maturation, DC cortical stiffness increases via a process that involves actin polymerization. Using stimulatory hydrogels and DCs expressing mutant cytoskeletal proteins, we find that increasing stiffness lowers the agonist dose needed for T cell activation. CD4+ T cells exhibit much more profound stiffness-dependency than CD8+ T cells. Finally, stiffness responses are most robust when T cells are stimulated with pMHC rather than anti-CD3ε, consistent with a mechanosensing mechanism involving receptor deformation. Taken together, our data reveal that maturation-associated cytoskeletal changes alter the biophysical properties of DCs, providing mechanical cues that costimulate T cell activation.

Article and author information

Author details

  1. Daniel Blumenthal

    Pathology and Laboratory Medicine, The Children's Hospital of Philadelphia Research Institute, Philadelphia, United States
    For correspondence
    daniel.blumenthal.chop@gmail.com
    Competing interests
    The authors declare that no competing interests exist.
  2. Vidhi Chandra

    Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3642-2144
  3. Lyndsay Avery

    Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Janis K Burkhardt

    Pathology and Laboratory Medicine, Children's Hospital of Philadelphia Research Institute, Philadelphia, United States
    For correspondence
    jburkhar@pennmedicine.upenn.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-8176-1375

Funding

National Institute of General Medical Sciences (GM104867)

  • Janis K Burkhardt

National Institute of Allergy and Infectious Diseases (AI32828)

  • Janis K Burkhardt

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 studies, breeding and maintenance of animals was performed under AnimalCare and Use Protocol #667, as approved by The Children's Hospital of Philadelphia Institutional Animal Care and Use Committee.

Reviewing Editor

  1. Michael L Dustin, University of Oxford, United Kingdom

Publication history

  1. Received: February 14, 2020
  2. Accepted: July 27, 2020
  3. Accepted Manuscript published: July 27, 2020 (version 1)

Copyright

© 2020, Blumenthal 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

  • 470
    Page views
  • 71
    Downloads
  • 0
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

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)

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

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

Further reading

    1. Biochemistry and Chemical Biology
    2. Cell Biology
    Catherine G Triandafillou et al.
    Research Article

    Heat shock induces a conserved transcriptional program regulated by heat shock factor 1 (Hsf1) in eukaryotic cells. Activation of this heat shock response is triggered by heat-induced misfolding of newly synthesized polypeptides, and so has been thought to depend on ongoing protein synthesis. Here, using the budding yeast Saccharomyces cerevisiae, we report the discovery that Hsf1 can be robustly activated when protein synthesis is inhibited, so long as cells undergo cytosolic acidification. Heat shock has long been known to cause transient intracellular acidification which, for reasons which have remained unclear, is associated with increased stress resistance in eukaryotes. We demonstrate that acidification is required for heat shock response induction in translationally inhibited cells, and specifically affects Hsf1 activation. Physiological heat-triggered acidification also increases population fitness and promotes cell cycle reentry following heat shock. Our results uncover a previously unknown adaptive dimension of the well-studied eukaryotic heat shock response.

    1. Cell Biology
    Vasyl Ivashov et al.
    Research Article

    How cells adjust nutrient transport across their membranes is incompletely understood. Previously, we have shown that S. cerevisiae broadly re-configures the nutrient transporters at the plasma membrane in response to amino acid availability, through endocytosis of sugar- and amino acid transporters (AATs) (Müller et al., 2015). A genome-wide screen now revealed that the selective endocytosis of four AATs during starvation required the α-arrestin family protein Art2/Ecm21, an adaptor for the ubiquitin ligase Rsp5, and its induction through the general amino acid control pathway. Art2 uses a basic patch to recognize C-terminal acidic sorting motifs in AATs and thereby instructs Rsp5 to ubiquitinate proximal lysine residues. When amino acids are in excess, Rsp5 instead uses TORC1-activated Art1 to detect N-terminal acidic sorting motifs within the same AATs, which initiates exclusive substrate-induced endocytosis. Thus, amino acid excess or starvation activate complementary α-arrestin-Rsp5-complexes to control selective endocytosis and adapt nutrient acquisition.