Title | The systemic immune state of super-shedder mice is characterized by a unique neutrophil-dependent blunting of TH1 responses. |
Publication Type | Journal Article |
Year of Publication | 2013 |
Authors | Gopinath, S, Hotson, A, Johns, JL, Nolan, G, Monack, D |
Journal | PLoS Pathog |
Volume | 9 |
Issue | 6 |
Pagination | e1003408 |
Date Published | 2013 |
ISSN | 1553-7374 |
Keywords | Animals, 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. |
DOI | 10.1371/journal.ppat.1003408 |
Alternate Journal | PLoS Pathog |
PubMed ID | 23754944 |
PubMed Central ID | PMC3675027 |
Grant List | HHSN272200700038C / AI / NIAID NIH HHS / United States T32 AI007328 / AI / NIAID NIH HHS / United States R01 A1095396 / / PHS HHS / United States HHSN272200700038C / / PHS HHS / United States |