Mechano-chemosensitive regulation of T cell migration by Filamin A via CXCR4 and β1 integrin dynamic remodeling

T cell migration is essential for immune surveillance and inflammation, and requires firm adhesion, crawling along the vascular endothelium, and transmigration. These events are tightly coordinated under blood flow by chemokine receptors and integrins. They are known to interact with the actin-binding scaffold Filamin A (FLNa), however, whether and how FLNa integrates chemotactic and mechanical cues to orchestrate their spatiotemporal organization during T cell migration under shear flow is not known. These questions are particularly challenging to address as receptor behavior must be captured dynamically at the nanoscale. By combining single-molecule tracking in CXCR4 and β1 integrin knock-in T cells, auxin-inducible FLNa degradation, and migration assays under physiological shear flow, we unveil how FLNa coordinates chemokine receptor and integrin regulation. FLNa is dispensable for CXCL12-induced CXCR4 nanoclustering but controls receptor dynamics and fast Rab4-dependent recycling. FLNa loss leads to the accumulation of enlarged CXCR4⁺/Rab4⁺ endosomes, delaying receptor recycling and reducing surface availability. In parallel, FLNa acts as a β1 integrin mechanosensitive organizer, promoting the formation of high-density nanoclusters required for stable adhesion under flow. Altogether, lack of FLNa weakens T cell adhesion and the data point at FLNa as a modulator of lymphocyte trafficking in physiological and disease contexts.