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

Abstract

SummaryThe 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.

Regulation of T‐lymphocyte motility, adhesion and de‐adhesion by a cell surface mechanism directed by low density lipoprotein receptor‐related protein 1 and endogenous thrombospondin‐1

“…These results confirm and extend previous findings that T‐cell motility is regulated by a counteradhesive motogenic mechanism directed by LRP1 and endogenous TSP‐1 . One important conclusion that can be drawn from the effects of ustekinumab is that motility and adhesion/spreading most likely are regulated at the cell surface level (Figs ).…”

“…The inhibitory effect on T‐cell motility of LRP1 knockdown coupled to enhancement of adhesion was previously shown to be mimicked by an inhibitor of the Janus kinase–signal transducer and activator of transcription 1 (JAK/STAT) pathway . The present results showed that ustekinumab mimicked LRP1 silencing and inhibition of the JAK/STAT pathway in its effects on motility and adhesion as well as in the enhancing effect on the expression of intact TSP‐1.…”

“…The TSP‐1 interaction with CD47 that promotes adhesion may seem inconsistent with the stimulatory effect on motility of the C‐terminal CD47 binding site in TSP‐1 alone . However, only intact TSP‐1 stimulates adhesion whereas the C‐terminal CD47 binding site inhibits adhesion (Fig.…”

Membrane-Associated Proteinase 3 on Granulocytes and Acute Myeloid Leukemia Inhibits T Cell Proliferation

“…Their association on PMN disrupts binding of CRT to LRP1 on macrophages and impairs CRT-LRP1-mediated phagocytosis (26). Moreover, LRP1 was shown to involve regulating T cell motility (27). Therefore we sought to determine whether mP3-expressing PMN-mediated T cell inhibition involved LRP1 on T cells.…”

Targeting CD47: the achievements and concerns of current studies on cancer immunotherapy

“…While the anti-CD47 mAb B6H12 disrupts the interaction between CD47 and SIRPα, it can also affect the binding of CD47 to SIRPγ (31) and thrombospondin1 (TSP1) (32). This implies that anti-CD47 therapy might involve functions of CD47 that are independent from SIRPα, which also provides an alternative explanation to the efficacy of CD47 shRNA (17).…”