title: The systemic immune state of super-shedder mice is characterized by a unique neutrophil-dependent blunting of TH1 responses.
abstract: Host-to-host transmission of a pathogen ensures its successful propagation and maintenance within a host population. A striking feature of disease transmission is the heterogeneity in host infectiousness. It has been proposed that within a host population, 20% of the infected hosts, termed super-shedders, are responsible for 80% of disease transmission. However, very little is known about the immune state of these super-shedders. In this study, we used the model organism Salmonella enterica serovar Typhimurium, an important cause of disease in humans and animal hosts, to study the immune state of super-shedders. Compared to moderate shedders, super-shedder mice had an active inflammatory response in both the gastrointestinal tract and the spleen but a dampened T(H)1 response specific to the secondary lymphoid organs. Spleens from super-shedder mice had higher numbers of neutrophils, and a dampened T cell response, characterized by higher levels of regulatory T cells (T(regs)), fewer T-bet(+) (T(H)1) T cells as well as blunted cytokine responsiveness. Administration of the cytokine granulocyte colony stimulating factor (G-CSF) and subsequent neutrophilia was sufficient to induce the super-shedder immune phenotype in moderate-shedder mice. Similar to super-shedders, these G-CSF-treated moderate-shedders had a dampened T(H)1 response with fewer T-bet(+) T cells and a loss of cytokine responsiveness. Additionally, G-CSF treatment inhibited IL-2-mediated TH1 expansion. Finally, depletion of neutrophils led to an increase in the number of T-bet(+) T(H)1 cells and restored their ability to respond to IL-2. Taken together, we demonstrate a novel role for neutrophils in blunting IL-2-mediated proliferation of the TH1 immune response in the spleens of mice that are colonized by high levels of S. Typhimurium in the gastrointestinal tract.
authors.affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.
authors.forename: Smita
authors.initials: S
authors.lastname: Gopinath
authors.forename: Andrew
authors.initials: A
authors.lastname: Hotson
authors.forename: Jennifer
authors.initials: J
authors.lastname: Johns
authors.forename: Garry
authors.initials: G
authors.lastname: Nolan
authors.forename: Denise
authors.initials: D
authors.lastname: Monack
mesh_terms: D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology; D051379:Mice; D009504:Neutrophils / Q000276:immunology* / Q000473:pathology; D012480:Salmonella Infections / Q000276:immunology* / Q000473:pathology; D012486:Salmonella typhimurium / Q000276:immunology*; D013154:Spleen / Q000276:immunology* / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology* / Q000473:pathology
chemical_list: D007376:Interleukin-2; D016179:Granulocyte Colony-Stimulating Factor