Integrins α3 and α6 promote Th17 cell migration by activating the purinergic receptor P2X4

Interactions of effector T cells with laminins during their trafficking across basement membranes play a crucial role in the development of the adaptive immune response and inflammatory diseases. However, the mechanisms involved in this process are not fully understood. In this study, we report that human Th17 cells express and use integrins α3 and α6 to migrate in laminin 10, which is predominant in basement membranes. We showed that laminin 10 induces via integrins α3 and α6, a sustained release of ATP from the mitochondria through pannexin-1 hemichannels, and that extracellular ATP is necessary for Th17 cell migration suggesting the implication of purinergic signaling. Inhibition studies identified a major role for the ionotropic purinergic receptor P2X4 in Th17 cell migration whereas purinergic receptors P2X7 and P2Y₁₁ had no role. Along these lines, our results showed that laminin 10 induced calcium entry into Th17 cells via the P2X4 receptor. Together these results show that integrins α3 and α6 induce Th17 cell migration by activating the P2X4 receptor. Our findings uncovered a crosstalk between laminin-binding integrins and purinergic signaling in promoting human Th17 cell migration and suggest that this pathway can play an important role in the immune response.