title: The CCR7 ligand elc (CCL19) is transcytosed in high endothelial venules and mediates T cell recruitment.
abstract: Lymphocyte homing to secondary lymphoid tissue is defined by a multistep sequence of interactions between lymphocytes and endothelial cells in high endothelial venules (HEVs). After initial selectin-mediated tethering and rolling, firm adhesion of lymphocytes requires rapid upregulation of lymphocyte integrin adhesiveness. This step is mediated in part by the HEV-derived chemokine SLC (secondary lymphoid-tissue chemokine, or CCL21) that binds to the CC chemokine receptor (CCR)7 on lymphocytes. However, the CC chemokine ELC (Epstein-Barr virus-induced molecule 1 ligand chemokine, or CCL19) shares the same receptor, and ELC transcripts have been observed in the T cell areas of lymphoid organs. Here, we show that perivascular ELC is transcytosed to the luminal surfaces of HEVs and enables efficient T cell homing to lymph nodes. In situ hybridization on sections of human tonsil showed no ELC mRNA in HEVs, but immunostaining revealed ELC protein in cytoplasmic vesicles of HEV cells. Furthermore, ELC injected into the footpads of mice entered the draining lymph nodes and was presented by HEVs. Finally, intracutaneous injections of ELC in mice lacking functionally relevant ELC and SLC (plt/plt mice) restored T cell trafficking to draining lymph nodes as efficiently as SLC. We conclude that perivascular ELC is transcytosed to the luminal surfaces of HEVs and participates in CCR7-mediated triggering of lymphocyte arrest.
authors.affiliation: Laboratory for Immunohistochemistry and Immunopathology (LIIPAT), Institute of Pathology, University of Oslo, Rikshospitalet, N-0027 Oslo, Norway. e.s.bakkevold@labmed.uio.no
authors.forename: E S
authors.initials: ES
authors.lastname: Baekkevold
authors.forename: T
authors.initials: T
authors.lastname: Yamanaka
authors.forename: R T
authors.initials: RT
authors.lastname: Palframan
authors.forename: H S
authors.initials: HS
authors.lastname: Carlsen
authors.forename: F P
authors.initials: FP
authors.lastname: Reinholt
authors.forename: U H
authors.initials: UH
authors.lastname: von Andrian
authors.forename: P
authors.initials: P
authors.lastname: Brandtzaeg
authors.forename: G
authors.initials: G
authors.lastname: Haraldsen
mesh_terms: D000818:Animals; D054415:Chemokine CCL19; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism*; D022162:Cytoplasmic Vesicles / Q000378:metabolism; D006801:Humans; D007267:Injections; D008024:Ligands; D008198:Lymph Nodes / Q000378:metabolism; D051379:Mice; D014066:Palatine Tonsil / Q000166:cytology; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019707:Receptors, Chemokine / Q000378:metabolism*; D013601:T-Lymphocytes / Q000502:physiology*; D014699:Venules / Q000378:metabolism*
chemical_list: C515460:CCL19 protein, human; C515370:CCR7 protein, human; C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D019742:Chemokines, CC; D008024:Ligands; D012333:RNA, Messenger; D054400:Receptors, CCR7; D019707:Receptors, Chemokine