Mycobacterium bovis BCG-Mediated Protection against W-Beijing Strains of Mycobacterium tuberculosis Is Diminished Concomitant with the Emergence of Regulatory T Cells

Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523-1682.
Clinical and vaccine Immunology: CVI (Impact Factor: 2.47). 07/2011; 18(9):1527-35. DOI: 10.1128/CVI.05127-11
Source: PubMed


Despite issues relating to variable efficacy in the past, the Mycobacterium bovis BCG vaccine remains the basis for new-generation recombinant vaccines currently in clinical trials. To date, vaccines have been tested mostly against laboratory strains and not against the newly emerging clinical strains. In this study, we evaluated the ability of BCG Pasteur to protect mice from aerosol infections with two highly virulent W-Beijing clinical strains, HN878 and SA161. In a conventional 30-day protection assay, BCG was highly protective against both strains, but by day 60 of the assay, this protection was diminished. Histological examination of the lungs of vaccinated animals showed reduced lung consolidation and smaller and more-organized granulomas in the vaccinated mice after 30 days, but in both cases, these tissues demonstrated worsening pathology over time. Effector T cell responses were increased in the vaccinated mice infected with HN878, but these diminished in number after day 30 of the infections concomitant with increased CD4(+) Foxp3(+) T cells in the lungs, draining lymph nodes, and the spleen. Given the concomitant decrease in effector immunity and continued expansion of regulatory Foxp3(+) cells observed here, it is reasonable to hypothesize that downregulation of effector immunity by these cells may be a serious impediment to the efficacy of BCG-based vaccines.

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Available from: Marcela I Henao-Tamayo, Oct 09, 2015
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    • "After infection with Mtb, Tregs are not only present in lymphoid organs, but are also recruited to lung granulomas in a TLR2-dependent manner [9], [13]. Likewise, Treg expansion has been also observed upon M. bovis Bacille Calmette-Guerin (BCG) vaccination and there is evidence that Tregs may correlate with the poor efficiency of this vaccine strain in conferring protection from pulmonary Tb [14], [15]. Particularly, BCG efficacy is lower in developing countries, where people are continuously exposed to low levels of environmental mycobacteria or helminth infections, both associated with high number of circulating Tregs [16], [17]. "
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    ABSTRACT: The development of an effective vaccine against tuberculosis (Tb) represents one of the major medical challenges of this century. Mycobacterium bovis Bacille Calmette-Guerin (BCG), the only vaccine available at present, is mostly effective at preventing disseminated Tb in children, but shows variable protection against pulmonary Tb, the most common form in adults. The reasons for this poor efficacy are not completely understood, but there is evidence that T regulatory cells (Tregs) might be involved. Similarly, Tregs have been associated with the immunosuppression observed in patients infected with Tb and are therefore believed to play a role in pathogen persistence. Thus, Treg depletion has been postulated as a novel strategy to potentiate M. bovis BCG vaccination on one side, while on the other, employed as a therapeutic approach during chronic Tb infection. Yet since Tregs are critically involved in controlling autoimmune inflammation, elimination of Tregs may therefore also incur the danger of an excessive inflammatory immune response. Thus, understanding the dynamics and function of Tregs during mycobacterial infection is crucial to evaluate the potential of Treg depletion as a medical option. To address this, we depleted Tregs after infection with M. bovis BCG or Mycobacterium tuberculosis (Mtb) using DEREG mice, which express the diphtheria toxin (DT) receptor under the control of the FoxP3 locus, thereby allowing the selective depletion of FoxP3+ Tregs. Our results show that after depletion, the Treg niche is rapidly refilled by a population of DT-insensitive Tregs (diTregs) and bacterial load remains unchanged. On the contrary, impaired rebound of Tregs in DEREG × FoxP3GFP mice improves pathogen burden, but is accompanied by detrimental autoimmune inflammation. Therefore, our study provides the proof-of-principle that, although a high degree of Treg depletion may contribute to the control of mycobacterial infection, it carries the risk of autoimmunity.
    PLoS ONE 07/2014; 9(7):e102804. DOI:10.1371/journal.pone.0102804 · 3.23 Impact Factor
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    • "In the animal models, animals are exposed to a relatively high dose, single exposure to a laboratory-adapted strain of M. tuberculosis. There are few data on the impact of novel vaccines against clinically relevant strains of M. tuberculosis [23–26]. One important question is whether challenging animals with relevant clinical isolates would improve the predictive value of these models, and more data on comparative efficacy against laboratory and clinical strains are needed. "
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    ABSTRACT: There is an urgent need for an improved TB vaccine. Vaccine development is hindered by the lack of immune correlates and uncertain predictive value of preclinical animal models. As data become available from human efficacy trials, there is an opportunity to evaluate the predictive value of the criteria used to select candidate vaccines. Here we review the efficacy in animal models of the MVA85A candidate vaccine in light of recent human efficacy data and propose refinements to the preclinical models with the aim of increasing their predictive value for human efficacy.
    Tuberculosis (Edinburgh, Scotland) 12/2013; 94(2). DOI:10.1016/ · 2.71 Impact Factor
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    • "MDSCs appear to be able to modulate T cell functions [41,42], and may possibly trigger regulatory T cells [38], an increasingly important subset in tuberculosis [3,43,44], and this could be interpreted as a mechanism to limit inflammation in the lungs and hence reduce lung damage. This is far from clear however, and while a report [41] shows protection against sepsis by adoptive transfer of these cells, another shows that transfer into normal mice damages the lungs [36]. "
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    ABSTRACT: Tuberculosis is one of the world's leading killers, stealing 1.4 million lives and causing 8.7 million new and relapsed infections in 2011. The only vaccine against tuberculosis is BCG which demonstrates variable efficacy in adults worldwide. Human infection with Mycobacterium tuberculosis results in the influx of inflammatory cells to the lung in an attempt to wall off bacilli by forming a granuloma. Gr1(int)CD11b(+) cells are called myeloid-derived suppressor cells (MDSC) and play a major role in regulation of inflammation in many pathological conditions. Although MDSC have been described primarily in cancer their function in tuberculosis remains unknown. During M. tuberculosis infection it is crucial to understand the function of cells involved in the regulation of inflammation during granuloma formation. Understanding their relative impact on the bacilli and other cellular phenotypes is necessary for future vaccine and drug design. We compared the bacterial burden, lung pathology and Gr1(int)CD11b(+) myeloid-derived suppressor cell immune responses in M. tuberculosis infected NOS2-/-, RAG-/-, C3HeB/FeJ and C57/BL6 mice. Gr-1(+) cells could be found on the edges of necrotic lung lesions in NOS2-/-, RAG-/-, and C3HeB/FeJ, but were absent in wild-type mice. Both populations of Gr1(+)CD11b(+) cells expressed high levels of arginase-1, and IL-17, additional markers of myeloid derived suppressor cells. We then sorted the Gr1(hi) and Gr1(int) populations from M. tuberculosis infected NOS-/- mice and placed the sorted both Gr1(int) populations at different ratios with naïve or M. tuberculosis infected splenocytes and evaluated their ability to induce activation and proliferation of CD4+T cells. Our results showed that both Gr1(hi) and Gr1(int) cells were able to induce activation and proliferation of CD4+ T cells. However this response was reduced as the ratio of CD4(+) T to Gr1(+) cells increased. Our results illustrate a yet unrecognized interplay between Gr1(+) cells and CD4(+) T cells in tuberculosis.
    PLoS ONE 11/2013; 8(11):e80669. DOI:10.1371/journal.pone.0080669 · 3.23 Impact Factor
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