Antigen‐induced regulation of T‐cell motility, interaction with antigen‐presenting cells and activation through endogenous thrombospondin‐1 and its receptors

Summary 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.