Trained immunity, tolerance, priming and differentiation: distinct immunological processes

Maziar Divangahi¹, Peter Aaby², Shabaana Abdul Khader³, Luis B Barreiro⁴, Siroon Bekkering⁵, Triantafyllos Chavakis⁶, Reinout van Crevel⁷, Nigel Curtis⁸, Andrew R DiNardo⁹, Jorge Dominguez-Andres⁷, Raphael Duivenvoorden^{10

11}, Stephanie Fanucchi¹², Zahi Fayad¹³, Elaine Fuchs¹⁴, Melanie Hamon¹⁵, Kate L Jeffrey¹⁶, Nargis Khan¹⁷, Leo A B Joosten^{7

18}, Eva Kaufmann¹⁷, Eicke Latz¹⁹, Giuseppe Matarese²⁰, Jos W M van der Meer²¹, Musa Mhlanga¹², Simone J C F M Moorlag^{7

19}, Willem J M Mulder^{10

11}, Shruti Naik²², Boris Novakovic²³, Luke O'Neill²⁴, Jordi Ochando²⁵, Keiko Ozato²⁶, Niels P Riksen⁵, Robert Sauerwein²⁷, Edward R Sherwood²⁸, Andreas Schlitzer^{29

30}, Joachim L Schultze³¹, Michael H Sieweke^{32

33

34}, Christine Stabell Benn^{35

36}, Henk Stunnenberg³⁷, Joseph Sun^{38

39}, Frank L van de Veerdonk⁴⁰, Sebastian Weis⁴¹, David L Williams⁴², Ramnik Xavier^{43

44

45}, Mihai G Netea^{46

47

48}

Affiliations

¹ Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University Health Centre and McGill International TB Centre, McGill University, Montreal, QC, Canada. maziar.divangahi@mcgill.ca.
² Bandim Health Project, Bissau, Guinea-Bissau.
³ Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA.
⁴ Department of Medicine, Genetic Section and, University of Chicago, Chicago, IL, USA.
⁵ Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
⁶ Institute for Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, Dresden, Germany.
⁷ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
⁸ Department of Paediatrics, Infectious Diseases Research Group, Murdoch Children's Research Institute, The University of Melbourne, Parkville, Victoria, Australia.
⁹ The Global Tuberculosis Program, Texas Children's Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁰ Biomedical Engineering and Imaging Institute and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Laboratory of Chemical Biology, Department of Biochemical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
¹² 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.
¹³ The BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY, USA.
¹⁵ Chromatine et Infection G5, Institut Pasteur, Paris, France.
¹⁶ Department of Medicine, Division of Gastroenterology and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University Health Centre and McGill International TB Centre, McGill University, Montreal, QC, Canada.
¹⁸ Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁹ Institute of Innate Immunity, University Hospitals Bonn and German Center for Neurodegenerative Diseases, Bonn, Germany.
²⁰ Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II" and Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy.
²¹ Radboud University Medical Center, Nijmegen, the Netherlands.
²² Department of Pathology, Department of Medicine and Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA.
²³ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
²⁴ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
²⁵ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Molecular Genetics of Immunity Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
²⁷ Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.
²⁸ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁹ Quantitative Systems Biology, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany.
³⁰ Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany.
³¹ Genomics & Immunoregulation, Life and Medical Sciences Bonn, University of Bonn, Bonn, Germany.
³² Aix Marseille University, CNRS, INSERM, CIML, Marseille, France.
³³ Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.
³⁴ Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany.
³⁵ Bandim Health Project, OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.
³⁶ Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark.
³⁷ Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, the Netherlands.
³⁸ Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁹ Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA.
⁴⁰ Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
⁴¹ Department of Anesthesiology and Intensive Care Medicine and Institute for Infectious Disease and Infection Control, Jena University Hospital, Jena, Germany.
⁴² Department of Surgery, Quillen College of Medicine and Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA.
⁴³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴⁴ Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴⁵ Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁶ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands. mihai.netea@radboudumc.nl.
⁴⁷ Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. mihai.netea@radboudumc.nl.
⁴⁸ Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. mihai.netea@radboudumc.nl.

PMID: 33293712
PMCID: PMC8020292
DOI: 10.1038/s41590-020-00845-6

Trained immunity, tolerance, priming and differentiation: distinct immunological processes

Maziar Divangahi et al. Nat Immunol. 2021 Jan.

. 2021 Jan;22(1):2-6.

doi: 10.1038/s41590-020-00845-6.

Authors

Affiliations

¹ Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University Health Centre and McGill International TB Centre, McGill University, Montreal, QC, Canada. maziar.divangahi@mcgill.ca.
² Bandim Health Project, Bissau, Guinea-Bissau.
³ Department of Molecular Microbiology, Washington University in St. Louis, St. Louis, MO, USA.
⁴ Department of Medicine, Genetic Section and, University of Chicago, Chicago, IL, USA.
⁵ Department of Internal Medicine and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
⁶ Institute for Clinical Chemistry and Laboratory Medicine, University Hospital, Technische Universität Dresden, Dresden, Germany.
⁷ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands.
⁸ Department of Paediatrics, Infectious Diseases Research Group, Murdoch Children's Research Institute, The University of Melbourne, Parkville, Victoria, Australia.
⁹ The Global Tuberculosis Program, Texas Children's Hospital, Immigrant and Global Health, Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA.
¹⁰ Biomedical Engineering and Imaging Institute and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹¹ Laboratory of Chemical Biology, Department of Biochemical Engineering, Eindhoven University of Technology, Eindhoven, the Netherlands.
¹² 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.
¹³ The BioMedical Engineering and Imaging Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
¹⁴ Laboratory of Mammalian Cell Biology and Development, Rockefeller University, New York, NY, USA.
¹⁵ Chromatine et Infection G5, Institut Pasteur, Paris, France.
¹⁶ Department of Medicine, Division of Gastroenterology and the Center for the Study of Inflammatory Bowel Disease, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
¹⁷ Meakins-Christie Laboratories, Department of Medicine, Department of Microbiology and Immunology, Department of Pathology, McGill University Health Centre and McGill International TB Centre, McGill University, Montreal, QC, Canada.
¹⁸ Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
¹⁹ Institute of Innate Immunity, University Hospitals Bonn and German Center for Neurodegenerative Diseases, Bonn, Germany.
²⁰ Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II" and Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli, Italy.
²¹ Radboud University Medical Center, Nijmegen, the Netherlands.
²² Department of Pathology, Department of Medicine and Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA.
²³ Murdoch Children's Research Institute and Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Victoria, Australia.
²⁴ School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.
²⁵ Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
²⁶ Molecular Genetics of Immunity Section, Division of Developmental Biology, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, USA.
²⁷ Radboudumc Center for Infectious Diseases, Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.
²⁸ Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
²⁹ Quantitative Systems Biology, Life & Medical Sciences Institute, University of Bonn, Bonn, Germany.
³⁰ Single Cell Genomics and Epigenomics Unit at the German Center for Neurodegenerative Diseases and the University of Bonn, Bonn, Germany.
³¹ Genomics & Immunoregulation, Life and Medical Sciences Bonn, University of Bonn, Bonn, Germany.
³² Aix Marseille University, CNRS, INSERM, CIML, Marseille, France.
³³ Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.
³⁴ Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany.
³⁵ Bandim Health Project, OPEN, Institute of Clinical Research, University of Southern Denmark/Odense University Hospital, Odense, Denmark.
³⁶ Danish Institute for Advanced Study, University of Southern Denmark, Odense, Denmark.
³⁷ Department of Molecular Biology, Faculty of Science, Radboud University, Nijmegen, the Netherlands.
³⁸ Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
³⁹ Department of Immunology and Microbial Pathogenesis, Weill Cornell Medical College, New York, NY, USA.
⁴⁰ Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands.
⁴¹ Department of Anesthesiology and Intensive Care Medicine and Institute for Infectious Disease and Infection Control, Jena University Hospital, Jena, Germany.
⁴² Department of Surgery, Quillen College of Medicine and Center of Excellence in Inflammation, Infectious Disease and Immunity, East Tennessee State University, Johnson City, TN, USA.
⁴³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴⁴ Center for Microbiome Informatics and Therapeutics, Massachusetts Institute of Technology, Cambridge, MA, USA.
⁴⁵ Center for Computational and Integrative Biology and Department of Molecular Biology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
⁴⁶ Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, the Netherlands. mihai.netea@radboudumc.nl.
⁴⁷ Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, the Netherlands. mihai.netea@radboudumc.nl.
⁴⁸ Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany. mihai.netea@radboudumc.nl.

PMID: 33293712
PMCID: PMC8020292
DOI: 10.1038/s41590-020-00845-6

Erratum in

Author Correction: Trained immunity, tolerance, priming and differentiation: distinct immunological processes.
Divangahi M, Aaby P, Khader SA, Barreiro LB, Bekkering S, Chavakis T, van Crevel R, Curtis N, DiNardo AR, Dominguez-Andres J, Duivenvoorden R, Fanucchi S, Fayad Z, Fuchs E, Hamon M, Jeffrey KL, Khan N, Joosten LAB, Kaufmann E, Latz E, Matarese G, van der Meer JWM, Mhlanga M, Moorlag SJCFM, Mulder WJM, Naik S, Novakovic B, O'Neill L, Ochando J, Ozato K, Riksen NP, Sauerwein R, Sherwood ER, Schlitzer A, Schultze JL, Sieweke MH, Benn CS, Stunnenberg H, Sun J, van de Veerdonk FL, Weis S, Williams DL, Xavier R, Netea MG. Divangahi M, et al. Nat Immunol. 2021 Jul;22(7):928. doi: 10.1038/s41590-021-00960-y. Nat Immunol. 2021. PMID: 34017127 No abstract available.

Abstract

The similarities and differences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the definition of trained immunity in both in vitro and in vivo settings, as well as in experimental models and human subjects, is necessary for advancing this field of research. Here we aim to establish a common framework that describes the experimental standards for defining trained immunity.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

**Fig. 1 |. Schematic presentation of the behavior of innate immune responses during the different adaptive programs induced in innate immune cells.**
a, Differentiation. b, Priming. c, Trained immunity (innate immune memory). d, Tolerance.

**Fig. 2 |**
Experimental models of in vitro and in vivo trained immunity.

See this image and copyright information in PMC

References

1. Netea MG et al. Nat. Rev. Immunol 20, 375–388 (2020). - PMC - PubMed
1. Netea MG, Schlitzer A, Placek K, Joosten LAB & Schultze JL Cell Host Microbe 25, 13–26 (2019). - PubMed
1. Kachroo A & Robin GP Curr. Opin. Plant Biol 16, 527–533 (2013). - PubMed
1. Di Luzio NR & Williams DL Infect. Immun 20, 804–810 (1978). - PMC - PubMed
1. Moorlag SJCFM et al. Cell Rep 31, 107634 (2020). - PMC - PubMed

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Trained immunity, tolerance, priming and differentiation: distinct immunological processes

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Trained immunity, tolerance, priming and differentiation: distinct immunological processes

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