Regulation of T‐lymphocyte motility,adhesion and de‐adhesion by a cell surface mechanism directed by low density lipoprotein receptor‐related protein 1 and endogenous thrombospondin‐1

T lymphocytes are highly motile and constantly reposition themselves between a free‐floating vascular state, transient adhesion and migration in tissues. The regulation behind this unique dynamic behaviour remains unclear. Here we show that T cells have a cell surface mechanism for integrated regulation of motility and adhesion and that integrin ligands and CXCL12/SDF‐1 influence motility and adhesion through this mechanism. Targeting cell surface‐expressed low‐density lipoprotein receptor‐related protein 1 (LRP1) with an antibody, or blocking transport of LRP1 to the cell surface, perturbed the cell surface distribution of endogenous thrombospondin‐1 (TSP‐1) while inhibiting motility and potentiating cytoplasmic spreading on intercellular adhesion molecule 1 (ICAM‐1) and fibronectin. Integrin ligands and CXCL12 stimulated motility and enhanced cell surface expression of LRP1, intact TSP‐1 and a 130 000 MW TSP‐1 fragment while preventing formation of a de‐adhesion‐coupled 110 000 MW TSP‐1 fragment. The appearance of the 130 000 MW TSP‐1 fragment was inhibited by the antibody that targeted LRP1 expression, inhibited motility and enhanced spreading. The TSP‐1 binding site in the LRP1‐associated protein, calreticulin, stimulated adhesion to ICAM‐1 through intact TSP‐1 and CD47. Shear flow enhanced cell surface expression of intact TSP‐1. Hence, chemokines and integrin ligands up‐regulate a dominant motogenic pathway through LRP1 and TSP‐1 cleavage and activate an associated adhesion pathway through the LRP1–calreticulin complex, intact TSP‐1 and CD47. This regulation of T‐cell motility and adhesion makes pro‐adhesive stimuli favour motile responses, which may explain why T cells prioritize movement before permanent adhesion.