Review

.2020 Jun;20(6):375-388.

doi: 10.1038/s41577-020-0285-6. Epub 2020 Mar 4.

Defining trained immunity and its role in health and disease

Mihai G Netea^{1 2 3}, Jorge Domínguez-Andrés^{4 5}, Luis B Barreiro^{6 7 8}, Triantafyllos Chavakis^{9 10}, Maziar Divangahi^{11 12 13}, Elaine Fuchs¹⁴, Leo A B Joosten^{4 5}, Jos W M van der Meer^{4 5}, Musa M Mhlanga^{15 16}, Willem J M Mulder^{17 18 19}, Niels P Riksen^{4 5}, Andreas Schlitzer²⁰, Joachim L Schultze²¹, Christine Stabell Benn²², Joseph C Sun^{23 24 25}, Ramnik J Xavier^{26 27}, Eicke Latz^{28 29 30}

Affiliations

¹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands. Mihai.Netea@radboudumc.nl.
² Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. Mihai.Netea@radboudumc.nl.
³ Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany. Mihai.Netea@radboudumc.nl.
⁴ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
⁵ Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
⁶ Department of Genetics, CHU Sainte-Justine Research Centre, Montreal, QC, Canada.
⁷ Department of Pediatrics, University of Montreal, Montreal, QC, Canada.
⁸ Genetics Section, Department of Medicine, The University of Chicago, Chicago, IL, USA.
⁹ Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany.
¹⁰ Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
¹¹ Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
¹² Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
¹³ McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada.
¹⁴ Howard Hughes Medical Institute, Robin Chemers Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA.
¹⁵ Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
¹⁶ Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal.
¹⁷ Translational and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, Netherlands.
²⁰ Myeloid Cell Biology, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
²¹ Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
²² Bandim Health Project, OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
²³ Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁴ Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁵ Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA.
²⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁷ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁸ Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany. eicke.latz@uni-bonn.de.
²⁹ Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA. eicke.latz@uni-bonn.de.
³⁰ German Center for Neurodegenerative Diseases, Bonn, Germany. eicke.latz@uni-bonn.de.

PMID:32132681
PMCID: PMC7186935
DOI: 10.1038/s41577-020-0285-6

Review

Defining trained immunity and its role in health and disease

Mihai G Netea et al. Nat Rev Immunol.2020 Jun.

.2020 Jun;20(6):375-388.

doi: 10.1038/s41577-020-0285-6. Epub 2020 Mar 4.

Authors

Affiliations

¹ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands. Mihai.Netea@radboudumc.nl.
² Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands. Mihai.Netea@radboudumc.nl.
³ Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany. Mihai.Netea@radboudumc.nl.
⁴ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands.
⁵ Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands.
⁶ Department of Genetics, CHU Sainte-Justine Research Centre, Montreal, QC, Canada.
⁷ Department of Pediatrics, University of Montreal, Montreal, QC, Canada.
⁸ Genetics Section, Department of Medicine, The University of Chicago, Chicago, IL, USA.
⁹ Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany.
¹⁰ Centre for Cardiovascular Science, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
¹¹ Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada.
¹² Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada.
¹³ McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada.
¹⁴ Howard Hughes Medical Institute, Robin Chemers Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA.
¹⁵ Division of Chemical and Systems Biology, Department of Integrative Biomedical Sciences, Faculty of Health Sciences, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, Cape Town, South Africa.
¹⁶ Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal.
¹⁷ Translational and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁸ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁹ Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, Netherlands.
²⁰ Myeloid Cell Biology, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
²¹ Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany.
²² Bandim Health Project, OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark.
²³ Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁴ Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
²⁵ Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA.
²⁶ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
²⁷ Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
²⁸ Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany. eicke.latz@uni-bonn.de.
²⁹ Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA. eicke.latz@uni-bonn.de.
³⁰ German Center for Neurodegenerative Diseases, Bonn, Germany. eicke.latz@uni-bonn.de.

PMID:32132681
PMCID: PMC7186935
DOI: 10.1038/s41577-020-0285-6

Abstract

Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.

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Conflict of interest statement

The authors declare no competing interests.

Figures

**Fig. 1. Trained immunity and tolerance: two opposite functional programmes of innate immunity.**
Infections or sterile tissue triggers induce inflammation and the activation of immune effector mechanisms. Concomitant to a proinflammatory response, anti-inflammatory mechanisms are provoked to prevent overshooting inflammation and tissue damage and to limit the inflammatory response in time. Trained immunity involves epigenetic and metabolic reprogramming of the innate immune cells, allowing qualitatively and quantitatively adjusted responses of innate immune cells to subsequent time-delayed heterologous stimulation. Misguided trained immunity responses can contribute to disease progression, resulting in either a chronic hyperinflammatory state or a persistent state of immunological tolerance, a mechanism that dampens the inflammatory response of the host to maintain homeostasis and prevent tissue damage and organ failure, with the subsequent risk of secondary infections and other diseases related to decreased activity of the immune system.

**Fig. 2. Central and peripheral trained immunity.**
Although trained immunity was first established in cells of the mononuclear phagocyte lineage (that is, monocytes and macrophages), monocytes have a relatively short lifespan and are unlikely to transmit their memory phenotype to their progeny and provide sustainable protection. Thus, current vaccine strategies that directly target monocytes or macrophages may have limited capacity for generating sustained innate immune memory. By contrast, haematopoietic stem cells (HSCs) are long-lived cells with self-renewal properties that reside in the bone marrow. The bone marrow is the site of haematopoiesis where HSCs continually undergo asymmetric division giving rise to the full repertoire of myeloid and lymphoid cell types. HSCs can directly respond to acute and chronic infections. Although the exact mechanisms of precursor proliferation or differentiation are not well understood, persistent activation of HSCs can result in their exhaustion, leading to devastating effects on the systemic immune compartment. Monocytes derived from trained HSCs migrate to peripheral organs, where they give rise to monocyte-derived macrophages with enhanced effector functions against different types of pathogens. Natural killer (NK) cells possess adaptive immune characteristics following infection. On reinfection, these memory NK cells undergo a secondary expansion and can more rapidly degranulate and release cytokines, resulting in a more protective immune response. Epithelial stem cells show memory functions during human allergic inflammatory disease, displaying changes in the chromatin accessibility when the stimulus is withdrawn. BCG, bacillus Calmette–Guérin; CMP, common myeloid progenitor: GMP, granulocyte–macrophage progenitor; MPP, multipotent progenitor.

**Fig. 3. Interplay between epigenetics and metabolism.**
The correct initiation of the mechanisms necessary for the induction of trained immunity relies on the active interplay between epigenetic and metabolic reprogramming of the innate immune cells on stimulation. During primary challenge, the recognition of specific ligands by pattern recognition receptors triggers a series of intracellular cascades that lead to the upregulation of different metabolic pathways, such as glycolysis, tricarboxylic acid (TCA) cycle and fatty acid metabolism. Certain metabolites derived from these processes, such as fumarate and acetyl coenzyme A (acetyl-CoA), can activate or inhibit a series of enzymes involved in remodelling the epigenetic landscape of cells, such as the histone demethylase lysine-specific demethylase 5 (KDM5) or histone acetyltransferases, leading to specific changes in histone methylation and acetylation of genes involved in the innate immune responses. β-Glucan-mediated activation of dectin 1 signalling also triggers calcium influx, which leads to the dephosphorylation of nuclear factor of activated T cells (NFAT), allowing its translocation into the nucleus, where it may bind to DNA and activate gene transcription. This facilitates the accessibility of the DNA to the transcriptional machinery and gene regulatory elements and specific long non-coding RNAs, promoting and facilitating an enhanced gene transcription on secondary stimulation of the cells. IGF1R, insulin-like growth factor 1 receptor; MLL1, mixed-lineage leukaemia protein 1 (also known as histone-lysineN-methyltransferase 2A); mTOR, mechanistic target of rapamycin; Pol, polymerase; UMLILO, upstream master long non-coding RNA of the inflammatory chemokine locus; WDR5, WD repeat-containing protein 5.

**Fig. 4. Epigenetic reprogramming underlies the induction of trained immunity.**
Stimulation of innate immune cells is accompanied by the deposition of chromatin marks and changes in the DNA methylation status, leading to unfolding of chromatin and facilitating transcription and expression of proinflammatory factors. All of these changes are only partially removed after cessation of the stimulus. This allows quicker and enhanced recruitment of transcription factors and gene expression after secondary challenge with another stimulus. The figure illustrates the chromatin states and epigenetic signatures associated with unstimulated cells, with cells following acute stimulation, with resting ‘trained’ cells and with trained cells following restimulation. H3K27ac, histone 3 lysine 27 acetylation; H3K4me, histone 3 lysine 4 methylation; H3K4me3, histone 3 lysine 4 trimethylation.

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Defining trained immunity and its role in health and disease

Affiliations

Defining trained immunity and its role in health and disease

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Conflict of interest statement

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