Thrombospondin‐1 Is a Contact Sensor Triggering Adhesion in T Cells and Platelets While Differentially Regulating 2D and 3D Motility in T Cells

The regulation of cell adhesion and motility is poorly understood. The present study uncovers a mechanism by which cells sense the microenvironment and regulate adhesion and motility. The C-terminal of TSP-1 was found to sense cell contact, which triggered N-terminal cleavage, adhesion, and cytoplasmic spreading in T cells and platelets on ICAM-1-coated surfaces. uPA was associated with TSP-1, an inhibitor of uPA antagonized cleavage, and zymography showed that uPA cleaves TSP-1, indicating that uPA caused the contact-triggered cleavage. In adhering T cells 2D, TSP-1 induced polar cell shape independent of LRP1, while interaction with LRP1 induced migration by internalizing TSP-1. In contrast, the development of polar cell shape, as well as migration 3D, was caused by direct interaction of TSP-1 with LRP1. Unlike its enhancing effect on polarity and migration 2D, contact sensing, and hence TSP-1 cleavage, inhibited 3D migration. Polar cell shape and migration, 2D and 3D, were driven by full-length TSP-1. CXCL12, which inhibits cleavage, stimulated migration. TSP-1 was limiting for ability of T cells to develop polar cell shape and migrate. These results indicate that TSP-1 is a contact sensor triggering adhesion in platelets and T cells, while driving and regulating motility in T cells.