The Systemic Immune State of Super-shedder Mice Is Characterized by a Unique Neutrophil-dependent Blunting of TH1 Responses

PLoS Pathogens

Jennifer Johns¹  Denise Monack²  Smita Gopinath²  Garry Nolan³  Andrew Hotson³ 

[1] Department of Comparative Medicine, Stanford University School of Medicine, Stanford, California, United States of America;Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America;Department of Microbiology and Immunology, The Baxter Laboratory of Genetic Pharmacology, Stanford University School of Medicine, Stanford, California, United States of America

关键词: T helper cells;    Neutrophils;    Salmonellosis;    Regulatory T cells;    Spleen;    Salmonella;    Immune response;    Mouse models;   

DOI  :  10.1371/journal.ppat.1003408

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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 TH1 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 (Tregs), fewer T-bet+ (TH1) 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 TH1 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+ TH1 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.

【 授权许可】

CC BY