{"doi":"10.1101/2023.09.26.559597","title":"Septins Enable T Cell Contact Guidance <i>via</i> Amoeboid-Mesenchymal Switch","abstract":"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. SIGNIFICANCE STATEMENT Deciphering mechanisms of guided lymphocyte migration paves the way towards effective immunotherapies for the extracellular matrix-rich tissues, such as solid tumors. Here we demonstrate that T cell septins’ GTPase activity regulates both actomyosin and microtubules, alternately enhancing either of these two major motor systems. Surprisingly, the suppression of septin GTPase activity also induces a highly guided integrin-dependent mesenchymal-like migration directed by the extracellular matrix proteins. The phenomenon of guided mesenchymal-like migration of T cells relies on the microtubules and microtubule-based dynein motors that are responsible for the force generation, powering guided T cell motility. This finding opens a new perspective for future studies of septin GTPases in a context of the optimisation of T cell-based immunotherapies for the solid tissues.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":397363,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":2,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9428,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":717606,"name":"Alexis Manning","orcid":null,"position":1,"is_corresponding":false},{"id":717117,"name":"Chynna Smith","orcid":"0009-0000-2740-1814","position":2,"is_corresponding":false},{"id":245814,"name":"Jian Wang","orcid":"0000-0001-7768-2802","position":3,"is_corresponding":false},{"id":379117,"name":"Xuefei Ma","orcid":"0000-0002-9665-8282","position":4,"is_corresponding":false},{"id":325622,"name":"Denis Tsygankov","orcid":"0000-0002-1180-3584","position":5,"is_corresponding":false},{"id":149320,"name":"Nikolay V. Dokholyan","orcid":"0000-0002-8225-4025","position":6,"is_corresponding":false},{"id":561055,"name":"Alexander X. Cartagena‐Rivera","orcid":"0000-0001-6227-2499","position":7,"is_corresponding":false},{"id":471670,"name":"Rakesh K. Singh","orcid":"0000-0002-1124-9202","position":8,"is_corresponding":false},{"id":442396,"name":"Erdem D. Tabdanov","orcid":"0000-0003-2673-112X","position":9,"is_corresponding":false},{"id":442397,"name":"Alexander S. Zhovmer","orcid":"0000-0003-3465-4953","position":0,"is_corresponding":true}],"reference_count":83,"raw_metadata":null,"created_at":"2026-07-19T01:19:39.497368Z","pmid":"37808814","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}