IFN-producing cells respond to CXCR3 ligands in the presence of CXCL12 and secrete inflammatory chemokines upon activation.
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.
Krug
Anne
A
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Uppaluri
Ravindra
R
Facchetti
Fabio
F
Dorner
Brigitte G
BG
Sheehan
Kathleen C F
KC
Schreiber
Robert D
RD
Cella
Marina
M
Colonna
Marco
M
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
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