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A6230 - Education of Stem Cells by BCG: An Innovative Approach in TB Vaccine Development
Author Block: E. Kaufmann1, J. Sanz2, J. L. Dunn1, N. Khan1, L. E. Mendonca1, A. Pacis2, F. Tzelepis1, E. Pernet1, A. Dumaine2, F. Mailhot-Léonard2, E. Ahmed1, J. Belle3, R. Besla4, B. D. Mazer1, I. L. King1, A. Nijnik3, C. S. Robbins4, L. B. Barreiro2, M. Divangahi1; 1Department of Medicine, McGill University, Montreal, QC, Canada, 2Department of Medicine, Université de Montréal, Montreal, QC, Canada, 3Department of Physiology, McGill University, Montreal, QC, Canada, 4Department of Immunology, University of Toronto, Toronto, ON, Canada.
RATIONALE To date, BCG is still the only available vaccine against TB, but prevents only the disseminated forms of the disease in early childhood. The efficacy of BCG against pulmonary TB in adults ranges from 0-80% (Fine, 1995). Although control of TB requires T cell-mediated immunity to prevent disease progression, a clinical trial using a T cell-targeting vaccine has failed to show protection against pulmonary Mtb infection (Tameris et al., 2013). We therefore hypothesize that a protective mechanism afforded by BCG in adults is mainly dependent on innate immune cells. Monocytes/Macrophages are one of the first cells to encounter Mycobacterium tuberculosis (Mtb) upon aerosol infection. However, considering the nature of monocyte/macrophage differentiation and their relatively short lifespan, we hypothesize that access of BCG to the bone marrow (BM) is required for educating hematopoietic stem cells (HSCs) to generate protective innate memory responses.
METHODS We use a mouse model of TB to investigate the impact of BCG vaccination on HSCs and monocytes/macrophages at both transcriptomic and epigenomic levels. Subsequently, by using chimeric mice, parabiosis, and an adoptive transfer model, we explore the protective capacities of monocytes/macrophages deriving from the “educated” HSCs during the course of pulmonary Mtb infection.
RESULTS We have demonstrated that BCG accesses the BM following intravenous but not subcutaneous vaccination. Interestingly, the presence of BCG in the BM significantly increased the total numbers of lineage-c-Kit+Sca1+ (LKS+) HSCs as well as multi-potent progenitors (MPPs). Importantly, BCG-induced HSC reprogramming led to the generation of epigenetically-modified monocytes/macrophages with tremendous protective capacities against subsequent Mtb infection. By using parabiosis and chimeric mice as well as adoptive transfer approaches, we demonstrate that BCG-induced HSC reprogramming leads to the education of monocytes/macrophages with sustainable protection against TB in vivo.
CONCLUSIONS Our findings demonstrate that access of BCG to the BM is critical for generating a unique set of educated monocytes/macrophages that are protective against virulent Mtb infection. Targeting the HSC compartment thus provides an innovative approach in TB-vaccine development.