Septins Enable T Cells Adaptive Circumnavigation and Migration-Transmigration Transition Within Structurally Complex Microenvironments

T cell all-terrain migration through healthy, inflamed or diseased tissues results from the dynamic balance between various migration modes. Here we report that septins mechanobiologically coordinate and balance amoeboid vs. mesenchymal-like migratory modes in T cells. Specifically, septins enable the assembly of circumferential cortical F-actin rings at the sites of cortex-indenting collisions with the extracellular matrix (ECM). Thus, septin rings compartmentalize the actomyosin cortex into a peristaltic chain of segments, spatially conformed to the ECM. Rings between adjacent spherical segments form ‘hourglass’-shaped furrows that sterically lock onto cortex-indenting collagen fibers, forming fulcrums for peristaltic treadmilling cytosolic content between cell compartments. Septins’ inactivation abruptly shifts T cells towards mesenchymal-like migration, characterized by the loss of amoeboid cortex compartmentalization, ineffective 3D circumnavigation, and distinct 2D contact guidance. We determine that mesenchymal-like lymphocyte migration is driven by dynein-based contractility within MAP4-, SEPT9-, HDAC6-enhanced microtubular cables for effective and structurally coherent motility and transmigration.GLOSSARYSteric interactions - interactions by the means of their spatial collision dependent on objects’ shapes.Steric guidance - cell navigation within crowded 3D environments, determined by the available passages around and between steric hindrances.Peristaltic treadmilling - locomotion mode by the means of a repeated sequence of polarized cell cortex extension, stabilization, and retraction, accompanied by translocation of nucleus and cytoplasm via circumferential cortex contractility.Dynein contractility - contractile forces generated by dynein motor proteins within a system of non-stretchable, force-transmitting microtubules.