Antigen-induced regulation of T-cell motility, interaction with antigen-presenting cells and activation through endogenous thrombospondin-1 and its receptors.
Antigen recognition reduces T-cell motility, and induces prolonged contact with antigen-presenting cells and activation through mechanisms that remain unclear. Here we show that the T-cell receptor (TCR) and CD28 regulate T-cell motility, contact with antigen-presenting cells and activation through endogenous thrombospondin-1 (TSP-1) and its receptors low-density lipoprotein receptor-related protein 1 (LRP1), calreticulin and CD47. Antigen stimulation induced a prominent up-regulation of TSP-1 expression, and transiently increased and subsequently decreased LRP1 expression whereas calreticulin was unaffected. This antigen-induced TSP-1/LRP1 response down-regulated a motogenic mechanism directed by LRP1-mediated processing of TSP-1 in cis within the same plasma membrane while promoting contact with antigen-presenting cells and activation through cis interaction of the C-terminal domain of TSP-1 with CD47 in response to N-terminal TSP-1 triggering by calreticulin. The antigen-induced TSP-1/LRP1 response maintained a reduced but significant motility level in activated cells. Blocking CD28 co-stimulation abrogated LRP1 and TSP-1 expression and motility. TCR/CD3 ligation alone enhanced TSP-1 expression whereas CD28 ligation alone enhanced LRP1 expression. Silencing of TSP-1 inhibited T-cell conjugation to antigen-presenting cells and T helper type 1 (Th1) and Th2 cytokine responses. The Th1 response enhanced motility and increased TSP-1 expression through interleukin-2, whereas the Th2 response weakened motility and reduced LRP1 expression through interleukin-4. Ligation of the TCR and CD28 therefore elicits a TSP-1/LRP1 response that stimulates prolonged contact with antigen-presenting cells and, although down-regulating motility, maintains a significant motility level to allow serial contacts and activation. Th1 and Th2 cytokine responses differentially regulate T-cell expression of TSP-1 and LRP1 and motility.
Department of Medicine, Karolinska Institute, Huddinge, Sweden; Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden; Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.
Sten-Erik
SE
Bergström
Mehmet
M
Uzunel
Toomas
T
Talme
Eva
E
Bergdahl
Karl-Gösta
KG
Sundqvist
D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism*; D000941:Antigens / Q000276:immunology / Q000378:metabolism*; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D018955:CD36 Antigens / Q000276:immunology / Q000378:metabolism*; D051928:CD47 Antigen / Q000276:immunology / Q000378:metabolism; D002450:Cell Communication; D002478:Cells, Cultured; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D010641:Phenotype; D034622:RNA Interference; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D058408:Th1-Th2 Balance; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D019700:Thrombospondin 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D014162:Transfection
D000941:Antigens; D018106:CD28 Antigens; D018955:CD36 Antigens; D051928:CD47 Antigen; C497894:CD47 protein, human; D016207:Cytokines; C475476:LRP1 protein, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D011948:Receptors, Antigen, T-Cell; D019700:Thrombospondin 1
T cells; cell activation; cell surface molecules