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 CD 28 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 ( LRP 1), calreticulin and CD 47. Antigen stimulation induced a prominent up‐regulation of TSP ‐1 expression, and transiently increased and subsequently decreased LRP 1 expression whereas calreticulin was unaffected. This antigen‐induced TSP ‐1/ LRP 1 response down‐regulated a motogenic mechanism directed by LRP 1‐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 CD 47 in response to N ‐terminal TSP ‐1 triggering by calreticulin. The antigen‐induced TSP ‐1/ LRP 1 response maintained a reduced but significant motility level in activated cells. Blocking CD 28 co‐stimulation abrogated LRP 1 and TSP ‐1 expression and motility. TCR / CD 3 ligation alone enhanced TSP ‐1 expression whereas CD 28 ligation alone enhanced LRP 1 expression. Silencing of TSP ‐1 inhibited T ‐cell conjugation to antigen‐presenting cells and T helper type 1 ( T h1) and T h2 cytokine responses. The T h1 response enhanced motility and increased TSP ‐1 expression through interleukin‐2, whereas the T h2 response weakened motility and reduced LRP 1 expression through interleukin‐4. Ligation of the TCR and CD 28 therefore elicits a TSP ‐1/ LRP 1 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. T h1 and T h2 cytokine responses differentially regulate T ‐cell expression of TSP ‐1 and LRP 1 and motility.