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ORIGINAL RESEARCH article

Front. Immunol.
Sec. T Cell Biology
Volume 15 - 2024 | doi: 10.3389/fimmu.2024.1467415

FMNL1 and mDia1 Promote Efficient T Cell Migration Through Complex Environments Via Distinct Mechanisms

Provisionally accepted
Ashton L. Sigler Ashton L. Sigler 1,2Scott B. Thompson Scott B. Thompson 1,2Logan Ellwood-Digel Logan Ellwood-Digel 1,2Adithan Kandasamy Adithan Kandasamy 3Mary J. Michaels-Foster Mary J. Michaels-Foster 1,2Dean Thumkeo Dean Thumkeo 4Shuh Narumiya Shuh Narumiya 4Juan Carlos Del Alamo Juan Carlos Del Alamo 3Jordan Jacobelli Jordan Jacobelli 1,2*
  • 1 Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • 2 The Barbara Davis Center for Diabetes, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
  • 3 University of Washington, Seattle, Washington, United States
  • 4 Kyoto University, Kyoto, Kyōto, Japan

The final, formatted version of the article will be published soon.

    Lymphocyte trafficking and migration through tissues is critical for adaptive immune function and, to perform their roles, T cells must be able to navigate through diverse tissue environments that present a range of mechanical challenges. T cells predominantly express two members of the formin family of actin effectors, Formin-like 1 (FMNL1) and mammalian diaphanous-related formin 1 (mDia1). While both FMNL1 and mDia1 have been studied individually, they have not been directly compared to determine functional differences in promoting T cell migration. Through in vivo analysis and the use of in vitro 2D and 3D model environments, we demonstrate that FMNL1 and mDia1 are both required for effective T cell migration, but they have different localization and roles in T cells, with specific environment-dependent functions. We found that mDia1 promotes general motility in 3D environments in conjunction with Myosin-II activity. We also show that, while mDia1 is almost entirely in the cytoplasmic compartment, a portion of FMNL1 physically associates with the nucleus. Furthermore, FMNL1 localizes to the rear of migrating T cells and contributes to efficient migration by promoting deformation of the rigid T cell nucleus in confined environments. Overall, our data indicates that while FMNL1 and mDia1 have similar mechanisms of actin polymerization, they have distinct roles in promoting T cell migration. This suggests that differential modulation of FMNL1 and mDia1 can be an attractive therapeutic route to fine-tune T cell migration behavior.

    Keywords: T cell, formins, Migration, motility, FMNL1, MDia1, DIAPH1, FRL1

    Received: 19 Jul 2024; Accepted: 13 Sep 2024.

    Copyright: © 2024 Sigler, Thompson, Ellwood-Digel, Kandasamy, Michaels-Foster, Thumkeo, Narumiya, Del Alamo and Jacobelli. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Jordan Jacobelli, Department of Immunology and Microbiology, School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, 80045, Colorado, United States

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.