title: Endotoxin augmented antigen-induced Th1 cell trafficking amplifies airway neutrophilic inflammation.
abstract: CD4(+) Th1 cells play a critical role in orchestrating host defense against pathogens and in the pathogenesis of many immune-mediated diseases. The control of Th1 cell trafficking into sites of infection and inflammation is an important determinant of Th1 cell function. We have previously shown that trafficking of adoptively transferred Ag-specific Th1 cells into the lung following airway Ag challenge depends on CXCR3 expression on Th1 cells and STAT1-inducible CXCR3 ligands in the lung. In this study, we show that LPS alters the mechanisms of Th1 cell recruitment. After a single intranasal dose of LPS, trafficking of adoptively transferred Ag-specific Th1 cell into the lung in response to airway Ag challenges was no longer dependent on CXCR3 and its ligands and instead was mediated through additional Galphai-coupled chemoattractant receptor pathways, including CCR5. In addition, LPS markedly increased the magnitude of Ag-specific Th1 cell homing into the airways following airway Ag challenges. The increased trafficking of Ag-activated Th1 cells, in turn, dramatically amplified LPS-induced airway neutrophilic infiltration by maintaining high levels of the neutrophil active chemokines, KC and MIP-2, through an IFN-gamma dependent mechanism. Therefore, LPS increases Ag-specific Th1 cell trafficking into the airways and Ag-specific Th1 cells amplify the airway neutrophilic inflammatory response initiated by LPS. This reciprocal interaction between LPS and Ag-activated Th1 cells represents a collaborative connection between the innate and adaptive arms of the immune system.
authors.affiliation: Division of Rheumatology, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02129, USA.
authors.forename: Zamaneh
authors.initials: Z
authors.lastname: Mikhak
authors.forename: Alireza
authors.initials: A
authors.lastname: Farsidjani
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Luster
mesh_terms: D000818:Animals; D000941:Antigens / Q000276:immunology*; D002465:Cell Movement / Q000187:drug effects / Q000276:immunology*; D004731:Endotoxins / Q000276:immunology*; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology; D008024:Ligands; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000276:immunology*; D011014:Pneumonia / Q000276:immunology* / Q000473:pathology; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D054367:Receptors, CXCR3 / Q000276:immunology / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology*
chemical_list: D000941:Antigens; C515188:Cxcr3 protein, mouse; D004731:Endotoxins; D008024:Ligands; D008070:Lipopolysaccharides; D019713:Receptors, CCR5; D054367:Receptors, CXCR3; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D007371:Interferon-gamma; D019206:GTP-Binding Protein alpha Subunits, Gi-Go