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The systemic immune state of super-shedder mice is characterized by a unique neutrophil-dependent blunting of TH1 responses.

Gopinath S, Hotson A, Johns J, Nolan G, Monack D - PLoS Pathog. (2013)

Bottom Line: 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.Typhimurium in the gastrointestinal tract.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.

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.

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Neutrophils control the dampened systemic TH1 response of super-shedders.In super-shedders, high levels of Salmonella in the gastrointestinal tract induce systemic neutrophilia with extensive granulopoiesis occurring in the bone marrow, resulting in elevated neutrophil counts in the blood, GI tract and spleen. This is accompanied by dampened IL-2 and IL-6 cytokine responsiveness in splenic CD4 T cells, fewer TH1 cells and more Tregs. In moderate shedders, low levels of gastrointestinal Salmonella induce very few neutrophils systemically, leading to an active IL-2 and IL-6 response with increased TH1 cells and fewer Tregs. Induction of granulopoiesis in moderate-shedders results in the super-shedder immune phenotype with the exception of Tregs, which remain unchanged.
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ppat-1003408-g007: Neutrophils control the dampened systemic TH1 response of super-shedders.In super-shedders, high levels of Salmonella in the gastrointestinal tract induce systemic neutrophilia with extensive granulopoiesis occurring in the bone marrow, resulting in elevated neutrophil counts in the blood, GI tract and spleen. This is accompanied by dampened IL-2 and IL-6 cytokine responsiveness in splenic CD4 T cells, fewer TH1 cells and more Tregs. In moderate shedders, low levels of gastrointestinal Salmonella induce very few neutrophils systemically, leading to an active IL-2 and IL-6 response with increased TH1 cells and fewer Tregs. Induction of granulopoiesis in moderate-shedders results in the super-shedder immune phenotype with the exception of Tregs, which remain unchanged.

Mentions: Our findings that both gastrointestinal Salmonella and G-CSF-mediated neutrophilia are associated with dampened IL-2 responsiveness in TH1 cells, suggest that neutrophil levels influence the ability of TH1 cells to expand. To investigate this, moderate-shedders were treated with G-CSF for 3 days, then subsequently administered IL-2 antibody complex for another 2 days, to determine the effect of neutrophilia on T cells expansion. After IL-2 antibody complex treatment, moderate-shedders pretreated with G-SCF had lower levels of both basal and IL-2 responsive pSTAT5+ CD4 T cells compared with mice that were not administered G-CSF (Figure 6C). This loss of IL-2 responsiveness correlated with significantly fewer Ki-67+ CD4 T cells (Fig. 6D), indicating that G-CSF treatment inhibited the ability of CD4 T cells to proliferate in response to IL-2. However, this inhibition was specific to TH1 cells, as G-CSF did not affect Treg expansion in response to IL-2 antibody complex (Figure 6E). This result is consistent with our previous finding that only TH1 cells and not Tregs expanded upon neutrophil depletion (Figure 4A, 4C). Thus, CD4 T cells in G-CSF treated moderate-shedders recapitulate the super-shedder phenotype. Taken together, we show that treatment of moderate-shedders with G-CSF is sufficient to recapitulate specific aspects of the super-shedder immune response (Figure 7).


The systemic immune state of super-shedder mice is characterized by a unique neutrophil-dependent blunting of TH1 responses.

Gopinath S, Hotson A, Johns J, Nolan G, Monack D - PLoS Pathog. (2013)

Neutrophils control the dampened systemic TH1 response of super-shedders.In super-shedders, high levels of Salmonella in the gastrointestinal tract induce systemic neutrophilia with extensive granulopoiesis occurring in the bone marrow, resulting in elevated neutrophil counts in the blood, GI tract and spleen. This is accompanied by dampened IL-2 and IL-6 cytokine responsiveness in splenic CD4 T cells, fewer TH1 cells and more Tregs. In moderate shedders, low levels of gastrointestinal Salmonella induce very few neutrophils systemically, leading to an active IL-2 and IL-6 response with increased TH1 cells and fewer Tregs. Induction of granulopoiesis in moderate-shedders results in the super-shedder immune phenotype with the exception of Tregs, which remain unchanged.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3675027&req=5

ppat-1003408-g007: Neutrophils control the dampened systemic TH1 response of super-shedders.In super-shedders, high levels of Salmonella in the gastrointestinal tract induce systemic neutrophilia with extensive granulopoiesis occurring in the bone marrow, resulting in elevated neutrophil counts in the blood, GI tract and spleen. This is accompanied by dampened IL-2 and IL-6 cytokine responsiveness in splenic CD4 T cells, fewer TH1 cells and more Tregs. In moderate shedders, low levels of gastrointestinal Salmonella induce very few neutrophils systemically, leading to an active IL-2 and IL-6 response with increased TH1 cells and fewer Tregs. Induction of granulopoiesis in moderate-shedders results in the super-shedder immune phenotype with the exception of Tregs, which remain unchanged.
Mentions: Our findings that both gastrointestinal Salmonella and G-CSF-mediated neutrophilia are associated with dampened IL-2 responsiveness in TH1 cells, suggest that neutrophil levels influence the ability of TH1 cells to expand. To investigate this, moderate-shedders were treated with G-CSF for 3 days, then subsequently administered IL-2 antibody complex for another 2 days, to determine the effect of neutrophilia on T cells expansion. After IL-2 antibody complex treatment, moderate-shedders pretreated with G-SCF had lower levels of both basal and IL-2 responsive pSTAT5+ CD4 T cells compared with mice that were not administered G-CSF (Figure 6C). This loss of IL-2 responsiveness correlated with significantly fewer Ki-67+ CD4 T cells (Fig. 6D), indicating that G-CSF treatment inhibited the ability of CD4 T cells to proliferate in response to IL-2. However, this inhibition was specific to TH1 cells, as G-CSF did not affect Treg expansion in response to IL-2 antibody complex (Figure 6E). This result is consistent with our previous finding that only TH1 cells and not Tregs expanded upon neutrophil depletion (Figure 4A, 4C). Thus, CD4 T cells in G-CSF treated moderate-shedders recapitulate the super-shedder phenotype. Taken together, we show that treatment of moderate-shedders with G-CSF is sufficient to recapitulate specific aspects of the super-shedder immune response (Figure 7).

Bottom Line: 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.Typhimurium in the gastrointestinal tract.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Stanford University School of Medicine, Stanford, California, United States of America.

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.

Show MeSH
Related in: MedlinePlus