A cytokine‐controlled mechanism for integrated regulation of T‐lymphocyte motility,adhesion and activation

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.