ABSTRACT
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.
GLOSSARY
Steric 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.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
The manuscript has been rewritten to reflect an addition of the new quantification data. The text and figures have been edited to improve the comprehensibility and accessibility for the general auditorium.