Stimpson, PJ; (2015) Early immune events in Mycobacterium tuberculosis infection and vaccination: protective role for GM-CSF in the primary immune response to Mycobacterium tuberculosis infection and recall responses following vaccination. Doctoral thesis , UCL (University College London).

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Abstract

Tuberculosis, caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb), is the second leading cause of death from infectious disease. BCG, the only licensed vaccine to date, only provides variable protection against pulmonary disease. Although there is a broad understanding of protective factors in the immune response to Mtb infection, including TNFα, IFNγ and the Th1 axis, these are incompletely understood, hindering development of novel vaccine regimes. Factors that are detrimental to control of Mtb infection, such as the immunosuppressive cytokine IL-10, are also induced upon Mtb infection and BCG vaccination. Blockade of the IL-10 receptor during BCG vaccination enhances protection in both resistant and susceptible mouse models of Mtb. Work in this thesis further investigated IL-10 mediated suppression of BCG-induced protection in Mtb susceptible mice and assessed how BCG vaccination in the context of IL-10 receptor blockade affected the onset of adaptive immunity. Vaccination in this context impacted the early immune response to Mtb challenge with accelerated and enhanced IL-17 and GM-CSF production. Furthermore, GM-CSF was required for optimal control of bacterial load upon Mtb challenge following BCG vaccination. GM-CSF was also required throughout primary Mtb infection as GM-CSF neutralisation was detrimental to control of bacterial load in both Mtb resistant and Mtb susceptible mouse models. Previous work showed IFNγ and IL-17 production by an “innate-like lymphoid” population upon Mtb challenge, following vaccination. This thesis further studied the response and role of ILCs in the early innate response to both the lab-adapted Mtb strain H37Rv and the clinical isolate HN878. ILCs were identified as a source of GM-CSF upon HN878 infection and were protective in the innate response to HN878 infection. Overall this thesis demonstrates the importance of GM-CSF in the primary and recall responses to Mtb infection and identifies ILCs as an early, innate source of GM-CSF.

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