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Title: Immune mechanisms of responses to environmental mycobacteria
Keywords: Environmental mycobacteria, Mycobacterium chelonae, BCG, Tuberculosis (TB), cytotoxicity, regulatory T cells (Treg)
Issue Date: 22-Mar-2011
Citation: HO PEIYING (2011-03-22). Immune mechanisms of responses to environmental mycobacteria. ScholarBank@NUS Repository.
Abstract: Human epidemiological studies suggest that poor efficacy of the tuberculosis (TB) vaccine, Mycobacterium bovis bacille Calmette- Guerin (BCG), may be because of immuno-modulatory effects of exposure to environmental mycobacteria (Env). However, exactly how and why this happens remains unclear. This study examined the hypothesis that effects of Env sensitisation are related to induction of regulatory and cytotoxic T cells. Mycobacterium chelonae (CHE) sensitisation of Balb/c mice through various routes was used as the model system. Heat-killed CHE intra-peritoneal sensitisation induced CD4+ T cells which lysed BCG-infected macrophages in vitro. The cytotoxicity was dependent on IFN-gamma, perforin and FasL. Sensitisation with an unrelated bacterium failed to induce cytotoxicity, therefore priming of T cells cross-reactive with BCG, and not non-specific inflammation, underlies the cytotoxicity. Sensitised mice had reduced BCG viability in the lungs upon subsequent inhalation challenge; this can explain the reduced BCG-induced protection. Both IFN-gamma and IL-10 were increased in the lungs of CHE-sensitised mice, relative to naive mice, after BCG lung challenge. Although the frequency of systemic CD4+CD25+ cells was unremarkable after CHE sensitisation, adoptive transfer of these Tregs to naive mice followed by BCG challenge led to reduced lung lymphocyte recruitment, reduced lung IL-2 and increased systemic IL-10 production. This suggests functional suppression of local BCG responses by CD4+CD25+ Tregs from CHE-sensitised mice. Memory responses after transient CHE lung colonisation led to increases in Tregs weeks after no live CHE was recoverable. Different doses of inhaled CHE exposure were tested ? higher doses induced stronger Treg responses and weaker BCG-specific IFN-gamma responses. Subsequent experiments used repeated low dose live intra-tracheal CHE exposure to mimic natural human inhalational exposure, followed by subcutaneous BCG vaccination. Systemic IL-10, mainly produced by CD4+CD25-FoxP3+ inducible Tregs, was increased and associated with reduced frequency of IFN-gamma producing memory cells recognising a BCG-specific epitope. Thus, adaptive Tregs also have a role in suppressing BCG-specific inflammation in CHE-sensitised mice. To explore if post-BCG CHE exposure had similar effects, BCG vaccination of weanling mice was followed by low dose CHE intra-tracheal exposures. This mainly induced natural Tregs, with minimal IL-10 induction. Suppression of inflammatory cell recruitment in the lungs to subsequent BCG lung challenge was noted, associated with reduced lung chemokines, in spite of elevated systemic IFN-gamma responses. The rate of inflammatory cell recruitment to the lung early in TB infection is increasingly recognised as the critical determinant of effective immunity, more than systemic IFN-gamma responses. Thus, CHE exposure even after BCG vaccination can suppress Mycobacterium-specific immunity. These two mechanisms proposed for effects of CHE exposure on BCG-induced immunity are novel. This work is also the first to provide a mechanistic explanation for how Env exposure modulates an existing BCG vaccine response. This accounts for observations of lack of BCG-induced protection in humans living in Env-prevalent areas, and suggests how prospective candidate TB vaccines could be screened to avoid problems of BCG vaccine. It also explains why even early neonatal BCG vaccination fails to provide long-lasting effects against adult pulmonary TB, with implications for its continued use.
Appears in Collections:Ph.D Theses (Open)

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