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Title: Regulatory T cell control of immune responses during acute Streptococcus pyogenes infection
Author: Chong, Deborah Lai Wah
ISNI:       0000 0004 2715 3090
Awarding Body: Imperial College London
Current Institution: Imperial College London
Date of Award: 2012
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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.
Supervisor: Altmann, Danny Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral