1. Cell Biology
  2. Immunology and Inflammation

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
https://doi.org/10.7554/eLife.58046
Share this article
Cite this article
  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
  2. Download BibTeX
  3. Download .RIS

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.

Metrics

  • 1,772
    Page views
  • 234
    Downloads
  • 15
    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)

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. 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

Categories and tags

Research organism

Further reading

    1. Cancer Biology
    2. Cell Biology

    ahctf1 and kras mutations combine to amplify oncogenic stress and restrict liver overgrowth in a zebrafish model of hepatocellular carcinoma

    Kimberly J Morgan, Karen Doggett ... Joan K Heath
    Research Article Updated

    The nucleoporin (NUP) ELYS, encoded by AHCTF1, is a large multifunctional protein with essential roles in nuclear pore assembly and mitosis. Using both larval and adult zebrafish models of hepatocellular carcinoma (HCC), in which the expression of an inducible mutant kras transgene (krasG12V) drives hepatocyte-specific hyperplasia and liver enlargement, we show that reducing ahctf1 gene dosage by 50% markedly decreases liver volume, while non-hyperplastic tissues are unaffected. We demonstrate that in the context of cancer, ahctf1 heterozygosity impairs nuclear pore formation, mitotic spindle assembly, and chromosome segregation, leading to DNA damage and activation of a Tp53-dependent transcriptional programme that induces cell death and cell cycle arrest. Heterozygous expression of both ahctf1 and ranbp2 (encoding a second nucleoporin), or treatment of heterozygous ahctf1 larvae with the nucleocytoplasmic transport inhibitor, Selinexor, completely blocks krasG12V-driven hepatocyte hyperplasia. Gene expression analysis of patient samples in the liver hepatocellular carcinoma (LIHC) dataset in The Cancer Genome Atlas shows that high expression of one or more of the transcripts encoding the 10 components of the NUP107–160 subcomplex, which includes AHCTF1, is positively correlated with worse overall survival. These results provide a strong and feasible rationale for the development of novel cancer therapeutics that target ELYS function and suggest potential avenues for effective combinatorial treatments.

    1. Cell Biology
    2. Immunology and Inflammation

    Spatially resolved transcriptomics reveals pro-inflammatory fibroblast involved in lymphocyte recruitment through CXCL8 and CXCL10

    Ana J Caetano, Yushi Redhead ... Paul T Sharpe
    Research Article Updated

    The interplay among different cells in a tissue is essential for maintaining homeostasis. Although disease states have been traditionally attributed to individual cell types, increasing evidence and new therapeutic options have demonstrated the primary role of multicellular functions to understand health and disease, opening new avenues to understand pathogenesis and develop new treatment strategies. We recently described the cellular composition and dynamics of the human oral mucosa; however, the spatial arrangement of cells is needed to better understand a morphologically complex tissue. Here, we link single-cell RNA sequencing, spatial transcriptomics, and high-resolution multiplex fluorescence in situ hybridisation to characterise human oral mucosa in health and oral chronic inflammatory disease. We deconvolved expression for resolution enhancement of spatial transcriptomic data and defined highly specialised epithelial and stromal compartments describing location-specific immune programs. Furthermore, we spatially mapped a rare pathogenic fibroblast population localised in a highly immunogenic region, responsible for lymphocyte recruitment through CXCL8 and CXCL10 and with a possible role in pathological angiogenesis through ALOX5AP. Collectively, our study provides a comprehensive reference for the study of oral chronic disease pathogenesis.

    1. Cell Biology
    2. Developmental Biology

    Peroxiredoxin 5 regulates osteogenic differentiation through interaction with hnRNPK during bone regeneration

    Eunjin Cho, Xiangguo Che ... Tae-Hoon Lee
    Research Article

    Peroxiredoxin 5 (Prdx5) is involved in pathophysiological regulation via the stress-induced cellular response. However, its function in the bone remains largely unknown. Here, we show that Prdx5 is involved in osteoclast and osteoblast differentiation, resulting in osteoporotic phenotypes in Prdx5 knockout (Prdx5Ko) male mice. To investigate the function of Prdx5 in the bone, osteoblasts were analyzed through immunoprecipitation (IP) and liquid chromatography combined with tandem mass spectrometry (LC–MS/MS) methods, while osteoclasts were analyzed through RNA-sequencing. Heterogeneous nuclear ribonucleoprotein K (hnRNPK) was identified as a potential binding partner of Prdx5 during osteoblast differentiation in vitro. Prdx5 acts as a negative regulator of hnRNPK-mediated osteocalcin (Bglap) expression. In addition, transcriptomic analysis revealed that in vitro differentiated osteoclasts from the bone marrow-derived macrophages of Prdx5Ko mice showed enhanced expression of several osteoclast-related genes. These findings indicate that Prdx5 might contribute to the maintenance of bone homeostasis by regulating osteoblast differentiation. This study proposes a new function of Prdx5 in bone remodeling that may be used in developing therapeutic strategies for bone diseases.