Redford, P.S.; (2007) Regulatory mechanisms inhibiting anti-mycobacterial immunity following Mycobacterium tuberculosis infection. Doctoral thesis , University of London.

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Abstract

The work reported in this thesis addresses the regulatory factors that function to limit the initiation of protective immune responses following exposure to the bacterium Mycobacterium tuberculosis (MTb). Control and clearance of intracellular pathogens, such as MTb, is dependent on the cytokine Tumour Necrosis Factor (TNF) and induction of a T-helper 1 (Thl) response, which is characterised by production of IFN-gamma driven by interleukin (IL)-12. In other infection models the presence of the immunosuppressive cytokine IL-10 in the local milieu has been shown to down-regulate Thl responses thus limiting detrimental host induced immune-pathology. To determine a role for IL-10 following murine infection, we examined its function during acute and chronic infections with two strains of H37Rv obtained from either i) National Institute for Medical Research (NIMR) or ii) London School of Hygiene and Tropical Medicine (LSHTM). IL-10 receptor blockade during the chronic phase of MTb infection reduced bacterial burdens in mice infected with H37Rv NIMR, but not mice infected with H37Rv LSHTM. However, despite the lack of effect of IL-10 blockade on the bacterial load during chronic infection with H37Rv LSHTM, immune cells obtained from MTb infected mice produced elevated levels of IFN-gamma when stimulated in vitro in the presence of IL-10 blocking antibodies. In addition, neutralisation of IL-10 before and during acute MTb infection with H37Rv LSHTM resulted in a transient reduction in bacterial burdens and enhanced IFN-gamma production, suggesting that IL-10 plays a role in regulating the early immune response to MTb. Additional regulators that may function together with or in parallel to IL-10 to limit bacterial clearance such as regulatory T cells (Tregs) have been shown to be regulators of autoimmunity, atopy and infectious disease. Using flow cytometric analysis of the Treg specific transcription factor FoxP3, we observed an early increase in the number of lung Tregs following aerosol MTb infection of mice. However, when addressing the effect on bacterial clearance in the absence of Tregs by either i) antibody depletion or ii) adoptive transfer approaches into immuno-deficient mice, a suppressive role for Tregs on bacterial burdens could not be found. Finally this work evaluated the role of plasmacytoid precursor DC (pDC) during MTb infection, which is in contrast their normal function as mediators of the anti viral response. Upon in vitro exposure to viable MTb, plasmacytoid pDC could not be infected and did not produce pro-inflammatory cytokines. Using flow cytometry, we observed no increase in plasmacytoid pDC in either the lung or spleen during the early stages of aerosol or intravenous infection. In addition, antibody depletion of plasmacytoid pDC during the early stages of MTb infection did not affect bacterial load. In summary, the data suggests that plasmacytoid pDC play only a minor role during the early immune response to MTb.

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