Septins Enable T Cell Contact Guidance via Amoeboid-Mesenchymal Switch

• Type of Material: Article
• Authors: Alexander S. Zhovmer, U.S. Food and Drug Administration; Alexis Manning, U.S. Food and Drug Administration; Chynna Smith, National Institutes of Health; Jian Wang, The Pennsylvania State University, Hershey; Xuefei Ma, U.S. Food and Drug Administration; Denis Tsygankov, Emory University; Nikolay V. Dokholyan, The Pennsylvania State University, Hershey; Alexander X. Cartagena-Rivera, National Institutes of Health; Rakesh K. Singh, University of Rochester; Erdem D. Tabdanov, The Pennsylvania State University, Hershey
• Language: English
• Date: 2023-09-27
• Publisher: NIH
• Publication Version: Preprint (Prior to Peer Review)
• Copyright Statement: The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.1101/2023.09.26.559597
• Title of Journal or Parent Work: bioRxiv
• Start Page: 559597
• Grant/Funding Information: E.D.T. and this work were supported by the Department of Pharmacology, Penn State College of Medicine via the startup funds. N.V.D. is supported by the NIH grant R35GM134864 and the Passan Foundation. D.T. is supported by the National Science Foundation (CMMI 1942561) and the National Institutes of Health (R01GM136892). A.S.Z., X.M., and A.M. were supported by the FDA Intramural Research Program of the Center for Biologics Evaluation and Research. A.X.C.R. and C.S. were supported by the National Institutes of Health (NIH) Intramural Research Program in the National Institute of Biomedical Imaging and Bioengineering (NIH grant # ZIA EB000094) and by the NIH Distinguished Scholars Program.
• Keywords: dynein; septin; migration; guidance; lymphocyte
• Research Categories: Biology, Molecular; Health Sciences, Immunology; Biology, Cell

Abstract

Lymphocytes exit circulation and enter in-tissue guided migration toward sites of tissue pathologies, damage, infection, or inflammation. By continuously sensing and adapting to the guiding chemo-mechano-structural properties of the tissues, lymphocytes dynamically alternate and combine their amoeboid (non-adhesive) and mesenchymal (adhesive) migration modes. However, which mechanisms guide and balance different migration modes are largely unclear. Here we report that suppression of septins GTPase activity induces an abrupt amoeboid-to-mesenchymal transition of T cell migration mode, characterized by a distinct, highly deformable integrin-dependent immune cell contact guidance. Surprisingly, the T cell actomyosin cortex contractility becomes diminished, dispensable and antagonistic to mesenchymal-like migration mode. Instead, mesenchymal-like T cells rely on microtubule stabilization and their non-canonical dynein motor activity for high fidelity contact guidance. Our results establish septin’s GTPase activity as an important on/off switch for integrin-dependent migration of T lymphocytes, enabling their dynein-driven fluid-like mesenchymal propulsion along the complex adhesion cues.