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Cell. 2018 Jan 11;172(1-2):176-190.e19. doi: 10.1016/j.cell.2017.12.031.

BCG Educates Hematopoietic Stem Cells to Generate Protective Innate Immunity against Tuberculosis.

Author information

1
Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada.
2
Department of Biochemistry, Faculty of Medicine, Université de Montréal, QC H3T 1J4, Canada; Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
3
Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada.
4
Department of Physiology, Complex Traits Group, McGill University, Montreal, QC H3G 0B1, Canada.
5
Department of Immunology, University of Toronto, Toronto, ON M5G 1L7, Canada.
6
Department of Genetics, CHU Sainte-Justine Research Center, Montreal, QC H3T 1C5, Canada; Department of Pediatrics, Faculty of Medicine, Université de Montréal, Montreal, QC H3T 1C5, Canada. Electronic address: luis.barreiro@umontreal.ca.
7
Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill International TB Centre, McGill University Health Centre, Montreal, QC H4A 3J1, Canada. Electronic address: maziar.divangahi@mcgill.ca.

Abstract

The dogma that adaptive immunity is the only arm of the immune response with memory capacity has been recently challenged by several studies demonstrating evidence for memory-like innate immune training. However, the underlying mechanisms and location for generating such innate memory responses in vivo remain unknown. Here, we show that access of Bacillus Calmette-Guérin (BCG) to the bone marrow (BM) changes the transcriptional landscape of hematopoietic stem cells (HSCs) and multipotent progenitors (MPPs), leading to local cell expansion and enhanced myelopoiesis at the expense of lymphopoiesis. Importantly, BCG-educated HSCs generate epigenetically modified macrophages that provide significantly better protection against virulent M. tuberculosis infection than naïve macrophages. By using parabiotic and chimeric mice, as well as adoptive transfer approaches, we demonstrate that training of the monocyte/macrophage lineage via BCG-induced HSC reprogramming is sustainable in vivo. Our results indicate that targeting the HSC compartment provides a novel approach for vaccine development.

KEYWORDS:

BCG; epigenetic reprogramming; macrophages; mycobacterium tuberculosis; stem cells; trained immunity

PMID:
29328912
DOI:
10.1016/j.cell.2017.12.031

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