title: The acquired immune response to the mucosal adjuvant LTK63 imprints the mouse lung with a protective signature.
abstract: LTK63, a nontoxic mutant of Escherichia coli heat labile enterotoxin (LT), is a potent and safe mucosal adjuvant that has also been shown to confer generic protection to several respiratory pathogens. To understand the mechanisms of action underlying the LTK63 protective effect, we analyzed the molecular and cellular events triggered by its administration in vivo. We show here that LTK63 intrapulmonary administration induced in the mouse lung a specific gene expression signature characterized by the up-regulation of cell cycle genes, several host defense genes, chemokines, chemokine receptors, and immune cell-associated genes. Such a transcriptional profile reflected the activation of alveolar macrophages and the recruitment to the lung of T and B cells and innate immune cells such as granulocytes, NK, and dendritic cells. All of these events were T cell dependent and specific for LTK63 because they were absent in SCID and nude mice. Additionally, we showed that LTK63 induces a potent adaptive immune response against itself directed to the lung. We propose that acquired response to LTK63 is the driving force for the local recruitment of both adaptive and innate immune cells. Our data suggest that LTK63 acts as an airway infection mimic that establishes a generic protective environment limiting respiratory infection by innate immune mechanisms and by improving adaptive responses to invading pathogens.
authors.affiliation: Novartis Vaccines and Diagnostics, Siena, Italy.
authors.forename: Elaine
authors.initials: E
authors.lastname: Tritto
authors.forename: Alessandro
authors.initials: A
authors.lastname: Muzzi
authors.forename: Isabella
authors.initials: I
authors.lastname: Pesce
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Monaci
authors.forename: Sandra
authors.initials: S
authors.lastname: Nuti
authors.forename: Grazia
authors.initials: G
authors.lastname: Galli
authors.forename: Andreas
authors.initials: A
authors.lastname: Wack
authors.forename: Rino
authors.initials: R
authors.lastname: Rappuoli
authors.forename: Tracy
authors.initials: T
authors.lastname: Hussell
authors.forename: Ennio
authors.initials: E
authors.lastname: De Gregorio
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D016175:B-Lymphocyte Subsets / Q000276:immunology; D001427:Bacterial Toxins / Q000008:administration & dosage* / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D018925:Chemokines / Q000096:biosynthesis / Q000235:genetics; D004768:Enterotoxins / Q000008:administration & dosage* / Q000276:immunology*; D029968:Escherichia coli Proteins / Q000008:administration & dosage* / Q000276:immunology*; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D007111:Immunity, Cellular; D007113:Immunity, Innate; D018928:Immunity, Mucosal; D007442:Intubation, Intratracheal; D008168:Lung / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D008213:Lymphocyte Activation / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D014158:Transcription, Genetic / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; D018925:Chemokines; D004768:Enterotoxins; D029968:Escherichia coli Proteins; C027538:heat-labile enterotoxin, E coli