title: IFN-producing cells respond to CXCR3 ligands in the presence of CXCL12 and secrete inflammatory chemokines upon activation.
abstract: Human natural IFN-producing cells (IPC) circulate in the blood and cluster in chronically inflamed lymph nodes around high endothelial venules (HEV). Although L-selectin, CXCR4, and CCR7 are recognized as critical IPC homing mediators, the role of CXCR3 is unclear, since IPC do not respond to CXCR3 ligands in vitro. In this study, we show that migration of murine and human IPC to CXCR3 ligands in vitro requires engagement of CXCR4 by CXCL12. We also demonstrate that CXCL12 is present in human HEV in vivo. Moreover, after interaction with pathogenic stimuli, murine and human IPC secrete high levels of inflammatory chemokines. Thus, IPC migration into inflamed lymph nodes may be initially mediated by L-selectin, CXCL12, and CXCR3 ligands. Upon pathogen encounter, IPC positioning within the lymph node may be further directed by CCR7 and IPC secretion of inflammatory chemokines may attract other IPC, promoting cluster formation in lymph nodes.
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Krug
authors.forename: Ravindra
authors.initials: R
authors.lastname: Uppaluri
authors.forename: Fabio
authors.initials: F
authors.lastname: Facchetti
authors.forename: Brigitte G
authors.initials: BG
authors.lastname: Dorner
authors.forename: Kathleen C F
authors.initials: KC
authors.lastname: Sheehan
authors.forename: Robert D
authors.initials: RD
authors.lastname: Schreiber
authors.forename: Marina
authors.initials: M
authors.lastname: Cella
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
mesh_terms: D000818:Animals; D054377:Chemokine CXCL12; D018925:Chemokines / Q000096:biosynthesis; D019743:Chemokines, CXC / Q000378:metabolism* / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte; D006801:Humans; D066298:In Vitro Techniques; D018836:Inflammation Mediators / Q000378:metabolism; D007372:Interferons / Q000096:biosynthesis*; D019041:L-Selectin / Q000378:metabolism; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology*; D008024:Ligands; D008198:Lymph Nodes / Q000166:cytology / Q000276:immunology; D051379:Mice; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000378:metabolism*; D014699:Venules / Q000166:cytology / Q000276:immunology
chemical_list: C515255:CXCL12 protein, human; C515187:CXCR3 protein, human; D054377:Chemokine CXCL12; D018925:Chemokines; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; C515188:Cxcr3 protein, mouse; D018836:Inflammation Mediators; D008024:Ligands; D054367:Receptors, CXCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D019041:L-Selectin; D007372:Interferons