title: Systemic administration of TLR3 agonist induces IL-7 expression and IL-7-dependent CXCR3 ligand production in the lung.
abstract: In this study, we tested the hypothesis that systemic administration of TLR3 agonist poly I:C can enhance T cell infiltration of lung through up-regulating IL-7 expression. poly I:C, a synthetic analog of viral dsRNA and a TLR3 agonist, is studied extensively as vaccine adjuvant as a result of its pleotropic immune-stimulatory effects. Here, we show that systemic poly I:C administration induces substantial IL-7 production in the lung in a type 1 IFN- and IFN-γ-dependent fashion. Blockade of the IL-7Rα signal with a neutralizing antibody abrogated poly I:C-induced MCP-1 up-regulation, macrophage recruitment, and CXCR3 ligand expression in the lung. Conversely, administration of IL-7 enhances these events, and it does so by enhancing T cell IFN-γ production. We also show that the initial up-regulation of CXCR3 ligands and infiltration of T cells in the lung are mediated by poly I:C-induced IFN-γ from NK cells; however, the sustained and optimal CXCR3 ligand expression and T cell infiltration require poly I:C-induced IL-7 and T cell-derived IFN-γ. In a model of multiorgan inflammation elicited by adoptive transfer of immune cells into RAG1(-/-) mice, we show that poly I:C enhances IL-7 production in the lung and promotes expression of CXCR3 ligands and recruitment of IFN-γ(+) T cells in an IL-7-dependent fashion. Collectively, these results strongly support our hypothesis and delineate a new mechanism by which poly I:C boosts the T cell immune response in the lung by inducing local IL-7 production, which in turn, enhances T cell-derived IFN-γ to promote macrophage recruitment, CXCR3 ligand expression, and T cell infiltration.
authors.affiliation: Department of Immunology and Infectious Disease, The Forsyth Institute, 245 First St., Cambridge, MA 02142, USA.
authors.forename: Jun-O
authors.initials: JO
authors.lastname: Jin
authors.forename: Qing
authors.initials: Q
authors.lastname: Yu
mesh_terms: D000818:Animals; D018932:Chemokine CCL2 / Q000235:genetics / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D007111:Immunity, Cellular / Q000187:drug effects* / Q000276:immunology; D007369:Interferon Inducers / Q000494:pharmacology*; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology; D015851:Interleukin-7 / Q000235:genetics / Q000276:immunology*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology; D008168:Lung / Q000166:cytology / Q000276:immunology*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D011070:Poly I-C / Q000494:pharmacology*; D054367:Receptors, CXCR3 / Q000819:agonists / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology*; D051196:Toll-Like Receptor 3 / Q000819:agonists* / Q000235:genetics / Q000276:immunology; D015854:Up-Regulation / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
chemical_list: C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; C515188:Cxcr3 protein, mouse; D018398:Homeodomain Proteins; D007369:Interferon Inducers; D015851:Interleukin-7; D054367:Receptors, CXCR3; C519703:TLR3 protein, mouse; D051196:Toll-Like Receptor 3; C064658:RAG-1 protein; D007371:Interferon-gamma; D011070:Poly I-C