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

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.

The microbiome and immune memory formation

“…Trained immunity has recently been shown to modulate hematopoietic stem cells and progenitor cells in the bone marrow, illustrating how innate immune cells can “remember” an initial encounter despite their short lifespan in the periphery . Mitroulis et al .…”

Mechanisms of M. tuberculosis Immune Evasion as Challenges to TB Vaccine Design

“…Another recent study revealed the potential for protection against TB by trained innate immunity (Kaufmann et al, 2018). Intravenous M. bovis BCG stimulated expansion of hematopoietic stem cells (HSC), associated with epigenetic changes transmitted to their progeny, including multipotent progenitors and bone marrow-derived macrophages (Kaufmann et al, 2018).…”

Two to Tango: Dialog between Immunity and Stem Cells in Health and Disease

“…These effects appeared to be rooted in changes to chromatin, as macrophages from vaccinated mice retained activating histone modifications (H3K4me3 and H3K27ac) at genes associated with pathogen responses (Figure 4B). Importantly, adoptive transfer and parabiosis studies revealed that vaccine-induced memory is long lasting and autonomous to HSCs (Kaufmann et al, 2018). …”