TitleThe systemic immune state of super-shedder mice is characterized by a unique neutrophil-dependent blunting of TH1 responses.
Publication TypeJournal Article
Year of Publication2013
AuthorsGopinath, S, Hotson, A, Johns, JL, Nolan, G, Monack, D
JournalPLoS Pathog
Volume9
Issue6
Paginatione1003408
Date Published2013
ISSN1553-7374
KeywordsAnimals, Cell Proliferation, Female, Granulocyte Colony-Stimulating Factor, Interleukin-2, Mice, Neutrophils, Salmonella Infections, Salmonella typhimurium, Spleen, T-Lymphocytes, Regulatory, Th1 Cells
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.

DOI10.1371/journal.ppat.1003408
Alternate JournalPLoS Pathog.
PubMed ID23754944
PubMed Central IDPMC3675027
Grant ListT32 AI007328 / AI / NIAID NIH HHS / United States
HHSN272200700038C / / PHS HHS / United States
R01 A1095396 / / PHS HHS / United States