Mechanosensitive ACKR4 scavenges CCR7 chemokines to facilitate Tcell de-adhesion and passive transport by flow in inflamed afferent lymphatics.

Abstract

T cell migration via afferent lymphatics to draining lymph nodes (dLNs) depends on expression of CCR7 in Tcells and CCL21 in the lymphatic vasculature. Once Tcells have entered lymphatic capillaries, they slowly migrate into contracting collecting vessels. Here, lymph flow picks up, inducing Tcell detachment and rapid transport to the dLNs. We find that the atypical chemokine receptor 4 (ACKR4), which binds and internalizes CCL19 and CCL21, is induced by lymph flow in endothelial cells lining lymphatic collectors, enabling them to scavenge these chemokines. In the absence of ACKR4, migration of Tcells to dLNs in TPA-induced inflammation is significantly reduced. While entry into capillaries is not impaired, Tcells accumulate in the ACKR4-deficient dermal collecting vessel segments. Overall, our findings identify an ACKR4-mediated mechanism by which lymphatic collectors facilitate the detachment of lymph-borne Tcells in inflammation and their transition from crawling to free-flow toward the dLNs.