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

• Published in: Cell reports (Cambridge) Vol. 38; no. 5; p. 110334
• Main Authors: Friess, Mona C., Kritikos, Ioannis, Schineis, Philipp, Medina-Sanchez, Jessica Danielly, Gkountidi, Anastasia-Olga, Vallone, Angela, Sigmund, Elena C., Schwitter, Corina, Vranova, Martina, Matti, Christoph, Arasa, Jorge, Saygili Demir, Cansaran, Bovay, Esther, Proulx, Steven T., Tomura, Michio, Rot, Antal, Legler, Daniel F., Petrova, Tatiana V., Halin, Cornelia
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2022
• Subjects: ACKR4; afferent lymphatics; Animals; CCL21, CCL19; Cell Movement - physiology; chemokine scavenging; collecting vessels; de-adhesion; Dendritic Cells - metabolism; Endothelial Cells - metabolism; Humans; Inflammation - metabolism; lymph flow; Lymph Nodes - metabolism; Lymphatic Vessels - metabolism; mechanosensing; Mice; Receptors, CCR - metabolism; Receptors, CCR7 - metabolism; Skin - metabolism; T cell migration; T-Lymphocytes - metabolism; collecting vessels; chemokine scavenging; mechanosensing; afferent lymphatics; de-adhesion; ACKR4; T cell migration; lymph flow; CCL21, CCL19
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2022.110334

T cell migration via afferent lymphatics to draining lymph nodes (dLNs) depends on expression of CCR7 in T cells and CCL21 in the lymphatic vasculature. Once T cells have entered lymphatic capillaries, they slowly migrate into contracting collecting vessels. Here, lymph flow picks up, inducing T cell 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 T cells to dLNs in TPA-induced inflammation is significantly reduced. While entry into capillaries is not impaired, T cells 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 T cells in inflammation and their transition from crawling to free-flow toward the dLNs. [Display omitted] •ACKR4 is expressed in a flow-dependent manner in afferent lymphatic collectors•ACKR4 scavenges CCR7 ligands like CCL21 and removes them from the collector surface•Chemokine scavenging prevents T cell accumulation in inflamed dermal collectors•In the absence of ACKR4, T cell migration to draining lymph nodes is reduced Friess et al. report that ACKR4 is expressed in a flow-dependent manner in afferent lymphatic collectors, where it removes CCR7 ligands from the collector surface. In inflammation, migrating T cells accumulate in dermal ACKR4-deficient collectors and fail to efficiently de-adhere for flow-mediated, passive transport to draining lymph nodes.