β1 Integrin induces adhesion and migration of human Th17 cells via Pyk2-dependent activation of P2X4 receptor

Integrin-mediated T-cell adhesion and migration is a crucial step in immune response and autoimmune diseases. However, the underlying signalling mechanisms are not fully elucidated. In this study, we examined the implication of purinergic signalling, which has been associated with T-cell activation, in the adhesion and migration of human Th17 cells across fibronectin, a major matrix protein associated with inflammatory diseases. We showed that the adhesion of human Th17 cells to fibronectin induces, via beta 1 integrin, a sustained release of adenosine triphosphate (ATP) from the mitochondria through the pannexin-1 hemichannels. Inhibition of ATP release or its degradation with apyrase impaired the capacity of the cells to attach and migrate across fibronectin. Inhibition studies identified a major role for the purinergic receptor P2X4 in T-cell adhesion and migration but not for P2X7 or P2Y(11) receptors. Blockade of P2X4 but not P2X7 or P2Y(11) receptors reduced cell adhesion and migration by inhibiting activation of beta 1 integrins, which is essential for ligand binding. Furthermore, we found that beta 1 integrin-induced ATP release, P2X4 receptor transactivation, cell adhesion and migration were dependent on the focal adhesion kinase Pyk2 but not FAK. Finally, P2X4 receptor inhibition also blocked fibronectin-induced Pyk2 activation suggesting the existence of a positive feedback loop of activation between beta 1 integrin/Pyk2 and P2X4 purinergic signalling pathways. Our findings uncovered an unrecognized link between beta 1 integrin and P2X4 receptor signalling pathways for promoting T-cell adhesion and migration across the extracellular matrix.

Automated summary

In this study, we found that integrin-mediated signaling induces the release of ATP, promoting T-cell adhesion and migration across fibronectin. P2X4 receptor plays a key role in T-cell adhesion and migration, while P2X7 and P2Y(11) receptors have no effect. Furthermore, we discovered a positive feedback loop between beta 1 integrin and P2X4 receptor signaling pathways.