Formin-like 1 mediates effector T cell trafficking to inflammatory sites to enable T cell-mediated autoimmunity

  1. Scott B Thompson
  2. Adam M Sandor
  3. Victor Lui
  4. Jeffrey W Chung
  5. Monique M Waldman
  6. Robert A Long
  7. Miriam L Estin
  8. Jennifer L Matsuda
  9. Rachel S Friedman
  10. Jordan Jacobelli  Is a corresponding author
  1. University of Colorado School of Medicine, United States
  2. National Jewish Health, United States

Abstract

Lymphocyte migration is essential for the function of the adaptive immune system, and regulation of T cell entry into tissues is an effective therapy in autoimmune diseases. Little is known about the specific role of cytoskeletal effectors that mediate mechanical forces and morphological changes essential for migration in complex environments. We developed a new Formin-like-1 (FMNL1) knock-out mouse model and determined that the cytoskeletal effector FMNL1 is selectively required for effector T cell trafficking to inflamed tissues, without affecting naïve T cell entry into secondary lymphoid organs. Here, we identify a FMNL1-dependent mechanism of actin polymerization at the back of the cell that enables migration of the rigid lymphocyte nucleus through restrictive barriers. Furthermore, FMNL1-deficiency impairs the ability of self-reactive effector T cells to induce autoimmune disease. Overall, our data suggest that FMNL1 may be a potential therapeutic target to specifically modulate T cell trafficking to inflammatory sites.

Data availability

The data generated and analysed in this study are included in the manuscript and/or supporting files.

Article and author information

Author details

  1. Scott B Thompson

    Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Adam M Sandor

    Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Victor Lui

    Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Jeffrey W Chung

    Immunology and Microbiology / Barbara Davis Research Center, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Monique M Waldman

    Immunology and Microbiology / Barbara Davis Research Center, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Robert A Long

    Immunology and Microbiology / Barbara Davis Research Center, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Miriam L Estin

    Immunology and Microbiology, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Jennifer L Matsuda

    Genetics Core Facility, National Jewish Health, Denver, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Rachel S Friedman

    Immunology and Microbiology / Barbara Davis Research Center, University of Colorado School of Medicine, Aurora, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Jordan Jacobelli

    Immunology and Microbiology / Barbara Davis Research Center, University of Colorado School of Medicine, Aurora, United States
    For correspondence
    jordan.jacobelli@cuanschutz.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6612-6704

Funding

National Institute of Allergy and Infectious Diseases (R56AI105111)

  • Jordan Jacobelli

National Institute of Allergy and Infectious Diseases (R01AI125553)

  • Jordan Jacobelli

National Institute of Allergy and Infectious Diseases (R21AI119932)

  • Rachel S Friedman

JDRF (5-2013-200)

  • Rachel S Friedman
  • Jordan Jacobelli

National Institute of Allergy and Infectious Diseases (T32AI007405)

  • Scott B Thompson
  • Monique M Waldman
  • Miriam L Estin

National Multiple Sclerosis Society (PP1775)

  • Jordan Jacobelli

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication. The content of this work is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding agencies.

Ethics

Animal experimentation: All experiments involving mice were approved by the Institutional Animal Care and Use Committees of National Jewish Health (Protocol #AS2811-01-23) and the University of Colorado School of Medicine (Protocol #000937). All efforts were made to minimize mouse suffering.

Reviewing Editor

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

Publication history

  1. Received: April 18, 2020
  2. Accepted: June 7, 2020
  3. Accepted Manuscript published: June 8, 2020 (version 1)
  4. Version of Record published: June 22, 2020 (version 2)

Copyright

© 2020, Thompson 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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  1. Scott B Thompson
  2. Adam M Sandor
  3. Victor Lui
  4. Jeffrey W Chung
  5. Monique M Waldman
  6. Robert A Long
  7. Miriam L Estin
  8. Jennifer L Matsuda
  9. Rachel S Friedman
  10. Jordan Jacobelli
(2020)
Formin-like 1 mediates effector T cell trafficking to inflammatory sites to enable T cell-mediated autoimmunity
eLife 9:e58046.
https://doi.org/10.7554/eLife.58046

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