title: 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.
abstract: 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.
authors.forename: Toomas
authors.initials: T
authors.lastname: Talme
authors.forename: Eva
authors.initials: E
authors.lastname: Bergdahl
authors.forename: Karl-Gösta
authors.initials: KG
authors.lastname: Sundqvist
mesh_terms: D000818:Animals; D002448:Cell Adhesion; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000096:biosynthesis / Q000378:metabolism*; D051381:Rats; D013601:T-Lymphocytes / Q000166:cytology* / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000378:metabolism*
chemical_list: C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D019700:Thrombospondin 1