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Defining trained immunity and its role in health and disease

Nature Reviews Immunology volume 20, pages 375–388 (2020)Cite this article

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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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Fig. 1: Trained immunity and tolerance: two opposite functional programmes of innate immunity.
Fig. 2: Central and peripheral trained immunity.
Fig. 3: Interplay between epigenetics and metabolism.
Fig. 4: Epigenetic reprogramming underlies the induction of trained immunity.

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Acknowledgements

M.G.N. was supported by a Spinoza grant from the Netherlands Organization for Scientific Research and a European Research Council (ERC) Advanced Grant (no. 833247). E.F. is an Investigator of the Howard Hughes Medical Institute and is supported by grants from the US National Institutes of Health (R01-AR31737 and R01-AR050452) and New York State (C32585GG). J.C.S. is supported by the Ludwig Center for Cancer Immunotherapy, the American Cancer Society, the Burroughs Wellcome Fund and the US National Institutes of Health (AI100874, AI130043 and P30CA008748). E.L. is supported by grants from the Deutsche Forschungsgemeinschaft (SFBs 645, 670 and 1123; TRRs 83 and 57), a grant from the US National Institutes of Health (1R01HL112661) and an ERC Consolidator grant (InflammAct). J.L.S is supported by grants from the Deutsche Forschungsgemeinschaft (West German Genome Center grant, Central Coordination Unit of the national Next-Generation Sequencing Competence Network) and grants from the Helmholtz Gemeinschaft (Sparse2Big and AmPro) and the European Union (SYSCID, no. 733100). E.L., M.G.N., J.L.S. and A.S. are members of the Immuno-Sensation excellence cluster funded by the Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy (EXC2151 — 390873048). T.C. is supported by an ERC Consolidator grant (DEMETINL) and by grants from the Deutsche Forschungsgemeinschaft (SFB 1181, TRR-SFB 205 and TRR-SFB 127). N.P.R., L.A.B.J. and M.G.N. received funding from the European Union Horizon 2020 research and innovation programme under grant agreement no. 667837 and the IN-CONTROL grant from the Dutch Foundation Netherlands (CVON2012-03 and CVON2018-27). N.P.R. is a recipient of a grant from European Research Area Network on Cardiovascular Diseases Joint Transnational Call 2018, which is supported by the Dutch Heart Foundation (JTC2018, project MEMORY; 2018T093).

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Authors and Affiliations

  1. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, Netherlands

    Mihai G. Netea, Jorge Domínguez-Andrés, Leo A. B. Joosten, Jos W. M. van der Meer & Niels P. Riksen

  2. Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands

    Mihai G. Netea, Jorge Domínguez-Andrés, Leo A. B. Joosten, Jos W. M. van der Meer & Niels P. Riksen

  3. Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany

    Mihai G. Netea & Joachim L. Schultze

  4. Department of Genetics, CHU Sainte-Justine Research Centre, Montreal, QC, Canada

    Luis B. Barreiro

  5. Department of Pediatrics, University of Montreal, Montreal, QC, Canada

    Luis B. Barreiro

  6. Genetics Section, Department of Medicine, The University of Chicago, Chicago, IL, USA

    Luis B. Barreiro

  7. Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany

    Triantafyllos Chavakis

  8. Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of Edinburgh, Edinburgh, UK

    Triantafyllos Chavakis

  9. Meakins-Christie Laboratories, Department of Medicine, McGill University Health Centre, Montreal, QC, Canada

    Maziar Divangahi

  10. Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada

    Maziar Divangahi

  11. McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada

    Maziar Divangahi

  12. Howard Hughes Medical Institute, Robin Chemers Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA

    Elaine Fuchs

  13. 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

    Musa M. Mhlanga

  14. Gene Expression and Biophysics Unit, Instituto de Medicina Molecular, Faculdade de Medicina Universidade de Lisboa, Lisbon, Portugal

    Musa M. Mhlanga

  15. Translational and Molecular Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Willem J. M. Mulder

  16. Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Willem J. M. Mulder

  17. Laboratory of Chemical Biology, Department of Biomedical Engineering and Institute for Complex Molecular Systems, Eindhoven University of Technology, Eindhoven, Netherlands

    Willem J. M. Mulder

  18. Myeloid Cell Biology, Life and Medical Sciences Institute, University of Bonn, Bonn, Germany

    Andreas Schlitzer

  19. Bandim Health Project, OPEN, Department of Clinical Research, University of Southern Denmark, Odense, Denmark

    Christine Stabell Benn

  20. Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Joseph C. Sun

  21. Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    Joseph C. Sun

  22. Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA

    Joseph C. Sun

  23. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Ramnik J. Xavier

  24. Center for Computational and Integrative Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA

    Ramnik J. Xavier

  25. Institute of Innate Immunity, University Hospital, University of Bonn, Bonn, Germany

    Eicke Latz

  26. Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA, USA

    Eicke Latz

  27. German Center for Neurodegenerative Diseases, Bonn, Germany

    Eicke Latz

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  1. Mihai G. Netea
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  2. Jorge Domínguez-Andrés
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The authors contributed equally to all aspects of the article.

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Glossary

Pattern recognition receptors

(PRRs). Germline-encoded receptors that recognize pathogen-associated molecular patterns — evolutionarily conserved structures associated with pathogens such as viruses, bacteria, fungi and parasites — and damage-associated molecular patterns, which are exposed in damaged host tissues. There are four main families of PRRs: namely, Toll-like receptors, NOD-like receptors, C-type lectin receptors and RIG1-like receptors. Interaction of pathogen-associated molecular patterns with pattern recognition receptors mediates recognition of pathogens and triggers inflammation.

Bacillus Calmette–Guérin

(BCG). An attenuated form of the bacterium Mycobacterium bovis, which is the causative agent of bovine tuberculosis. Developed at Institut Pasteur at the beginning of the twentieth century as a vaccine to prevent tuberculosis (BCG vaccine), it also induces protective heterologous effects against infections and malignancies.

Myeloid cells

Cells of the immune system that arise from pluripotent primordial cells in the bone marrow. Myeloid cells (monocytes, macrophages, dendritic cells and granulocytes) have many physiological roles, among which are roles are to destroy the invading pathogens and repair tissues.

Chromatin

A complex structure composed of DNA and proteins located in the nucleus in which the genetic material of eukaryotic cells is organized. Chromatin has a high degree of organization, which allows the compaction of the genetic material, but this remains reachable to allow access of the protein machinery that regulates gene transcription. Chemical modification of histones, the core proteins in chromatin, regulates the accessibility of the DNA for the transcription machinery.

Topologically associated domains

(TADs). Large domains of about 0.5 to 2 million base pairs into which chromosomes rolled up in loops are organized, where different regions frequently interact with each other, allowing gene promoters to interact with all their regions’ regulators even over long distances. Within each TAD, several genes and the elements that regulate them are packaged together and are isolated from neighbouring TADs.

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Netea, M.G., Domínguez-Andrés, J., Barreiro, L.B. et al. Defining trained immunity and its role in health and disease. Nat Rev Immunol 20, 375–388 (2020). https://doi.org/10.1038/s41577-020-0285-6

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