title: A cytokine-controlled mechanism for integrated regulation of T-lymphocyte motility, adhesion and activation.
abstract: The co-ordination of T-cell motility, adhesion and activation remains poorly understood. It is also unclear how these functions are co-ordinated with external stimuli. Here we unveil a series of molecular interactions in cis at the surface of T lymphocytes with potent effects on motility and adhesion in these cells, and communicating with proliferative responses. These interactions were controlled by the signature cytokines of T helper subsets interleukin-2 (IL-2) and IL-4. Low-density lipoprotein receptor-related protein 1 (LRP1) was found to play a key role for T-cell motility by promoting development of polarized cell shape and cell movement. Endogenous thrombospondin-1 (TSP-1) enhanced cell surface expression of LRP1 through CD47. Cell surface expressed LRP1 induced motility and processing of TSP-1 while inhibiting adhesion to intercellular adhesion molecule 1 and fibronectin. Interleukin-2, but not IL-4, stimulated synthesis of TSP-1 and motility through TSP-1 and LRP1. Stimulation of the T-cell receptor (TCR)/CD3 complex inhibited TSP-1 expression. Inhibitor studies indicated that LRP1 regulated TSP-1 expression and promoted motility through JAK signalling. This LRP1-mediated motogenic signalling was connected to CD47/Gi protein signalling and IL-2-induced signalling through TSP-1. The motogenic TSP-1/LRP1 mechanism antagonized TCR/CD3-induced T-cell proliferation. These results indicate that LRP1 in collaboration with TSP-1 directs a counter-adhesive and counter-proliferative motogenic cascade. T cells seem programmed to prioritize movement before adhesion through this cascade. In conclusion, vital decision-making in T lymphocytes regulating motility, adhesive interactions and proliferation, are integrated through a molecular mechanism connecting different cell surface receptors and their signalling pathways.
authors.affiliation: Department of Medicine, Karolinska Institute, Huddinge, Sweden; Division of Clinical Immunology, Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Sten-Erik
authors.initials: SE
authors.lastname: Bergström
authors.forename: Eva
authors.initials: E
authors.lastname: Bergdahl
authors.forename: Karl-Gösta
authors.initials: KG
authors.lastname: Sundqvist
mesh_terms: D017252:CD3 Complex / Q000378:metabolism; D051928:CD47 Antigen / Q000378:metabolism; D037282:Calreticulin / Q000378:metabolism; D002448:Cell Adhesion; D049109:Cell Proliferation; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D053612:Janus Kinases / Q000378:metabolism; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C576483:CALR protein, human; D017252:CD3 Complex; D051928:CD47 Antigen; C497894:CD47 protein, human; D037282:Calreticulin; D016207:Cytokines; D005353:Fibronectins; C508594:IL2 protein, human; C508598:IL4 protein, human; D007376:Interleukin-2; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011948:Receptors, Antigen, T-Cell; D050791:STAT Transcription Factors; D019700:Thrombospondin 1; D018799:Intercellular Adhesion Molecule-1; D015847:Interleukin-4; D053612:Janus Kinases
keywords: MHC; lipoprotein receptor-related protein 1; lymphocytes; migration; thrombospondin-1