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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- 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
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
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