Regulatory T cell control of immune responses during acute Streptococcus pyogenes infection
Author(s)
Chong, Deborah Lai Wah
Type
Thesis
Abstract
Streptococcus pyogenes, also known as Group A Streptococci (GAS) causes many
diseases, ranging from non-invasive (“Strep throat) to highly invasive (bacterial
sepsis). GAS secretes various virulence factors implicated in pathogenesis and
immune evasion, the best studied include superantigens. Regulatory T cells (Tregs) are
a subset of CD4+ T cells, previously described in maintaining the fine balance of
immune responses during infectious diseases; however, the precise role during
streptococcal infection is unknown. The work in this thesis involves the
characterisation of Tregs in the pathogenesis of GAS infection. Depletion of Tregs in
inducible Foxp3.DTR knockout mice during GAS infection showed significant
reduction in systemic bacterial spread and decreased serum levels of proinflammatory
cytokines (IL-6 and IFN-γ), suggesting Tregs are detrimental to the host
response to this bacterium. Further examination of effector cells indicate a protective
role for CD8+, γδ+ T cells and NK cells in this model of acute sepsis as depletion of
either of these subsets exacerbated bacterial burden and altered cytokine production.
Utilising a transgenic HLA-DQ8.Aβ0 murine model, previously demonstrated to be
susceptible to streptococcal superantigens, up-regulation of Foxp3 gene and protein
expression in secondary lymphoid tissues during early stages of infection was
attributed to the presence of SMEZ superantigen, correlating with decreased bacterial
load. SPEA superantigen was found to induce TH1 cells and enhanced IFN-γ
production to lead to the so-called “cytokine storm” and increased bacterial burden.
This suggests that GAS through the action of secreted superantigens, modulates the
immune response to induce Tregs and establish a state of tolerance to hinder protective
effector cells, such as CD8+, γδ+ T cells and NK cells and IL-17A production, while
promoting pathogenic TH1 cells to drive potent immune pathology.
diseases, ranging from non-invasive (“Strep throat) to highly invasive (bacterial
sepsis). GAS secretes various virulence factors implicated in pathogenesis and
immune evasion, the best studied include superantigens. Regulatory T cells (Tregs) are
a subset of CD4+ T cells, previously described in maintaining the fine balance of
immune responses during infectious diseases; however, the precise role during
streptococcal infection is unknown. The work in this thesis involves the
characterisation of Tregs in the pathogenesis of GAS infection. Depletion of Tregs in
inducible Foxp3.DTR knockout mice during GAS infection showed significant
reduction in systemic bacterial spread and decreased serum levels of proinflammatory
cytokines (IL-6 and IFN-γ), suggesting Tregs are detrimental to the host
response to this bacterium. Further examination of effector cells indicate a protective
role for CD8+, γδ+ T cells and NK cells in this model of acute sepsis as depletion of
either of these subsets exacerbated bacterial burden and altered cytokine production.
Utilising a transgenic HLA-DQ8.Aβ0 murine model, previously demonstrated to be
susceptible to streptococcal superantigens, up-regulation of Foxp3 gene and protein
expression in secondary lymphoid tissues during early stages of infection was
attributed to the presence of SMEZ superantigen, correlating with decreased bacterial
load. SPEA superantigen was found to induce TH1 cells and enhanced IFN-γ
production to lead to the so-called “cytokine storm” and increased bacterial burden.
This suggests that GAS through the action of secreted superantigens, modulates the
immune response to induce Tregs and establish a state of tolerance to hinder protective
effector cells, such as CD8+, γδ+ T cells and NK cells and IL-17A production, while
promoting pathogenic TH1 cells to drive potent immune pathology.
Date Issued
2012
Date Awarded
2012-02
Copyright Statement
Attribution NoDerivatives 4.0 International Licence (CC BY-ND)
Advisor
Altmann, Danny
Publisher Department
Medicine
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)