BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment

Cirovic, Branko; Bree, L. Charlotte J. de; Groh, Laszlo; Blok, Bastiaan A.; Chan, Jane; Velden, Walter J.F.M. van der; Bremmers, M.E.J.; Crevel, Reinout van; Händler, Kristian; Picelli, Simone; Schulte-Schrepping, Jonas; Klee, Kathrin; Oosting, Marije; Koeken, Valerie A C M; Ingen, Jakko van; Li, Yang; Benn, Christine Stabell; Schultze, Joachim L.; Joosten, Leo A. B.; Curtis, Nigel; Netea, Mihai G.; Schlitzer, Andreas

doi:10.1016/j.chom.2020.05.014

Cited by 336 publications

(357 citation statements)

References 50 publications

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“…We also showed previously that hematopoietic stem cell transplantation from β-glucan-trained mice to naive recipients gives rise to increased frequency of neutrophils in the circulation of the latter ( Mitroulis et al., 2018 ). Our findings together with a recent study showing that changes in hematopoietic progenitors and in granulocytes are integral to BCG-induced trained immunity in humans ( Cirovic et al., 2020 ) point to the emerging and hitherto underappreciated role of neutrophils as effectors of trained immunity.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Kalafati

Kourtzelis

Schulte-Schrepping

et al. 2020

Cell

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Summary Trained innate immunity, induced via modulation of mature myeloid cells or their bone marrow progenitors, mediates sustained increased responsiveness to secondary challenges. Here, we investigated whether anti-tumor immunity can be enhanced through induction of trained immunity. Pre-treatment of mice with β-glucan, a fungal-derived prototypical agonist of trained immunity, resulted in diminished tumor growth. The anti-tumor effect of β-glucan-induced trained immunity was associated with transcriptomic and epigenetic rewiring of granulopoiesis and neutrophil reprogramming toward an anti-tumor phenotype; this process required type I interferon signaling irrespective of adaptive immunity in the host. Adoptive transfer of neutrophils from β-glucan-trained mice to naive recipients suppressed tumor growth in the latter in a ROS-dependent manner. Moreover, the anti-tumor effect of β-glucan-induced trained granulopoiesis was transmissible by bone marrow transplantation to recipient naive mice. Our findings identify a novel and therapeutically relevant anti-tumor facet of trained immunity involving appropriate rewiring of granulopoiesis.

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Section: Discussionmentioning

confidence: 99%

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Kalafati

Kourtzelis

Schulte-Schrepping

et al. 2020

Cell

Self Cite

376

323

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“…This is also observed in humans, with BCG vaccination imprinting a persistent myeloid transcriptomic bias on HSPCs. This is regulated by the hepatic nuclear factors HNF1a and HNF1b and results in persistent training of CD14 + monocytes (Cirovic et al, 2020).…”

Section: Trained Immunity Across Cell Types and Tissuesmentioning

confidence: 99%

Trained immunity and host‐pathogen interactions

Peignier

Parker

2020

Cellular Microbiology

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Infectious diseases are a leading cause of death worldwide with over 8 million fatalities accounted for in 2016. Solicitation of host immune defenses by vaccination is the treatment of choice to prevent these infections. It has long been thought that vaccine immunity was solely mediated by the adaptive immune system. However, over the past decade, numerous studies have shown that innate immune cells can also retain memory of these encounters. This process, called innate immune memory, is mediated by metabolic and epigenetic changes that make cells either hyperresponsive (trained immunity) or hyporesponsive (tolerance) to subsequent challenges. In this review, we discuss the concepts of trained immunity and tolerance in the context of host‐pathogen interactions.

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“…Considering that BCG reprograms HSCs toward myelopoiesis and generates protective trained immunity against Mtb ( Cirovic et al., 2020 ; Kaufmann et al., 2018 ), we investigated whether the presence of virulent Mtb in the BM affects innate immunity to infection. Here we show that, although access of Mtb to the BM changes the transcriptional landscape of HSCs and multipotent progenitors (MPPs) similarly to BCG, the magnitude of the IFN-I and heme metabolism pathways significantly differed between BCG and Mtb .…”

Section: Introductionmentioning

confidence: 99%

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity

Khan

Downey

Sanz

et al. 2020

Cell

184

179

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Summary A greater understanding of hematopoietic stem cell (HSC) regulation is required for dissecting protective versus detrimental immunity to pathogens that cause chronic infections such as Mycobacterium tuberculosis ( Mtb ). We have shown that systemic administration of Bacille Calmette-Guérin (BCG) or β-glucan reprograms HSCs in the bone marrow (BM) via a type II interferon (IFN-II) or interleukin-1 (IL1) response, respectively, which confers protective trained immunity against Mtb . Here, we demonstrate that, unlike BCG or β-glucan, Mtb reprograms HSCs via an IFN-I response that suppresses myelopoiesis and impairs development of protective trained immunity to Mtb . Mechanistically, IFN-I signaling dysregulates iron metabolism, depolarizes mitochondrial membrane potential, and induces cell death specifically in myeloid progenitors. Additionally, activation of the IFN-I/iron axis in HSCs impairs trained immunity to Mtb infection. These results identify an unanticipated immune evasion strategy of Mtb in the BM that controls the magnitude and intrinsic anti-microbial capacity of innate immunity to infection.

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BCG Vaccination in Humans Elicits Trained Immunity via the Hematopoietic Progenitor Compartment

Cited by 336 publications

References 50 publications

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Innate Immune Training of Granulopoiesis Promotes Anti-tumor Activity

Trained immunity and host‐pathogen interactions

M. tuberculosis Reprograms Hematopoietic Stem Cells to Limit Myelopoiesis and Impair Trained Immunity

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