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Trained immunity — basic concepts and contributions to immunopathology

Nature Reviews Nephrology volume 19, pages 23–37 (2023)Cite this article

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Abstract

Trained immunity is a functional state of the innate immune response and is characterized by long-term epigenetic reprogramming of innate immune cells. This concept originated in the field of infectious diseases — training of innate immune cells, such as monocytes, macrophages and/or natural killer cells, by infection or vaccination enhances immune responses against microbial pathogens after restimulation. Although initially reported in circulating monocytes and tissue macrophages (termed peripheral trained immunity), subsequent findings indicate that immune progenitor cells in the bone marrow can also be trained (that is, central trained immunity), which explains the long-term innate immunity-mediated protective effects of vaccination against heterologous infections. Although trained immunity is beneficial against infections, its inappropriate induction by endogenous stimuli can also lead to aberrant inflammation. For example, in systemic lupus erythematosus and systemic sclerosis, trained immunity might contribute to inflammatory activity, which promotes disease progression. In organ transplantation, trained immunity has been associated with acute rejection and suppression of trained immunity prolonged allograft survival. This novel concept provides a better understanding of the involvement of the innate immune response in different pathological conditions, and provides a new framework for the development of therapies and treatment strategies that target epigenetic and metabolic pathways of the innate immune system.

Key points

  • Trained immunity is a functional state of the innate immune system that is characterized by long-term epigenetic and metabolic reprogramming of cells associated with potent immune responses.

  • Experimental and clinical studies have demonstrated that exogenous pathogen-associated molecular patterns and endogenous danger-associated molecular patterns induce trained immunity.

  • Trained immunity is a functional adaptation of the innate immune system against secondary infections, but can lead to aberrant inflammatory activity in conditions such as autoimmunity.

  • Sterile inflammation owing to ischaemia–reperfusion injury and organ transplantation induces trained immunity and precipitates allograft rejection.

  • Therapeutic inhibition of trained immunity (for example, in autoimmunity or transplantation) or its induction (for example, in infections or cancer) are promising strategies for treating immunity-related diseases.

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Fig. 1: Differences between innate immune cell activation, priming, training and tolerance.
Fig. 2: Cellular, molecular, metabolic and epigenetic approaches to studying trained immunity.
Fig. 3: Proposed role of trained immunity in SLE.
Fig. 4: Trained immunity in kidney transplantation.
Fig. 5: Therapeutic targeting of trained immunity.

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Acknowledgements

The authors’ work is supported by National Institutes of Health grants R01 AI139623AI (J.O.); Vici grant from the Dutch Research Council (NWO) and European Research Council Advanced Grant (TOLERANCE) (W.J.M.M.); European Research Council Consolidator Grant (310372) and Spinoza Grant of the Netherlands Organization for Scientific Research (M.G.N.); P01 HL158504 (J.C.M.); and Hypatia grant by the Radboud University Medical Center and Senior Kolff grant by the Dutch Kidney Foundation (R.D.).

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Authors and Affiliations

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

    Jordi Ochando

  2. Transplant Immunology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Madrid, Spain

    Jordi Ochando

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

    Willem J. M. Mulder

  4. Biomedical Engineering and Imaging Institute, Department of Radiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA

    Willem J. M. Mulder & Raphaël Duivenvoorden

  5. Center for Transplantation Sciences, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

    Joren C. Madsen

  6. Division of Cardiac Surgery, Department of Surgery, Massachusetts General Hospital, Boston, MA, USA

    Joren C. Madsen

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

    Mihai G. Netea

  8. Department for Genomics & Immunoregulation, Life and Medical Sciences Institute (LIMES), University of Bonn, Bonn, Germany

    Mihai G. Netea

  9. Department of Nephrology, Radboud University Medical Center, Nijmegen, The Netherlands

    Raphaël Duivenvoorden

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All authors researched data for the article, made substantial contributions to discussions of the content and wrote, reviewed or edited the manuscript before submission.

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Correspondence to Jordi Ochando or Raphaël Duivenvoorden.

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J.O., W.J.M.M., and M.G.N. declare that they are scientific founders of Trained Therapeutics Discovery. The other authors declare no competing interests.

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Nature Reviews Nephrology thanks C. Kurts, X. Yang and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Ochando, J., Mulder, W.J.M., Madsen, J.C. et al. Trained immunity — basic concepts and contributions to immunopathology. Nat Rev Nephrol 19, 23–37 (2023). https://doi.org/10.1038/s41581-022-00633-5

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