REVIEWS Defining trained immunity and its role in health and disease Mihai G. Netea 1,2,3 ✉ , Jorge Domínguez- Andrés1,2, Luis B. Barreiro4,5,6, Triantafyllos Chavakis7,8, Maziar Divangahi9,10,11, Elaine Fuchs12, Leo A. B. Joosten1,2, Jos W. M. van der Meer1,2, Musa M. Mhlanga13,14, Willem J. M. Mulder15,16,17, Niels P. Riksen1,2, Andreas Schlitzer18, Joachim L. Schultze3, Christine Stabell Benn19, Joseph C. Sun20,21,22, Ramnik J. Xavier23,24 and Eicke Latz25,26,27 ✉ 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. Pattern recognition The vertebrate immune system has traditionally been called ‘LPS tolerance’, which can be induced by low receptors divided into innate and adaptive arms. Cells of the innate doses of lipopolysaccharide (LPS) and other Toll-like (PRRs). Germline- encoded immune system recognize pathogens and tissue damage receptor ligands, is also an adaptation of cellular receptors that recognize through germline- encoded pattern recognition receptors responses to an external stimulus, but which leads to a pathogen-associated molecular (PRRs)1,2, which sense diverse pathogen- associated lower inflammatory response to a second stimulation13. patterns — evolutionarily conserved structures molecular patterns and damage- associated molecular These studies have led to the hypothesis that the associated with pathogens patterns. The processes activated on engagement of PRRs innate immune system also exhibits adaptive characteris- such as viruses, bacteria, fungi are rapid, are considered to be non-specific and include tics, a property that has been termed ‘trained immunity’. and parasites — and responses such as phagocytosis, cell locomotion, killing Understanding the properties of trained immunity will damage- associated molecular patterns, which are exposed in of pathogens or cells, and cytokine production. These result in a better understanding of host defence mech- damaged host tissues. There innate immune mechanisms are usually very effective anisms and the pathogenesis of immune- mediated are four main families of PRRs: in eliminating invading pathogens. Additionally, den- diseases. The conceptual and mechanistic advances in namely, Toll- like receptors, dritic cells (DCs) and specialized T cells and B cells drive this emerging field of science will open new avenues for NOD- like receptors, C- type adaptive immune responses, which can be concomi- clinical applications in vaccination as well as for disease lectin receptors and RIG1- like receptors. Interaction of tantly induced. These lymphocyte- dependent adaptive prevention and treatment. In this Review, we discuss pathogen-associated molecular immune responses are slower to develop but are antigen the latest discoveries in the field of trained immunity patterns with pattern specific and lead to long-term immunological memory3. and highlight possible directions of future research in recognition receptors mediates For a long time it was assumed that immunological this field. recognition of pathogens and triggers inflammation. memory was an exclusive hallmark of the adaptive immune response. However, a growing body of liter- Defining trained immunity ature indicating that innate immune cells — and even The concept of trained immunity describes the long-term tissue-resident stem cells — can show adaptive charac- functional reprogramming of innate immune cells, teristics has challenged this dogma4–8. Greater protection which is evoked by exogenous or endogenous insults against reinfection — a de facto immune memory and which leads to an altered response towards a second function — has also been reported in plants and inver- challenge after the return to a non- activated state. The tebrates9–11, which lack an adaptive immune system. This secondary response to the subsequent non-specific stim- demonstrates that adaptation of host defence can occur ulus can be altered in such a way that the cells respond ✉e- mail: Mihai.Netea@ radboudumc.nl; eicke.latz@ on the basis of innate- like immune mechanisms. More- more or less strongly than to the primary response, con- uni- bonn.de over, certain infections and vaccinations can induce ferring context- adjusted and time- adjusted responses. https://doi.org/10.1038/ broad protection against other pathogens through innate It is important to underline that trained immunity rep- s41577-020-0285-6 immune mechanisms5,12. Conversely, the phenomenon resents the concept of long- term adaptation of innate NATURE REVIEWS | IMMUNOLOGY VOLUME 20 | JUNE 2020 | 375 REVIEWS Bacillus Calmette–Guérin immune cells rather than a particular transcriptional transgenerational effects through induction of trained 16,17 (BCG). An attenuated form of or functional programme: indeed, different stimuli (for immunity . the bacterium Mycobacterium example, β- glucan, LPS or the bacillus Calmette–Guérin bovis, which is the causative (BCG) vaccine) can induce different trained immunity Immune memory: an evolutionary perspective agent of bovine tuberculosis. Developed at Institut Pasteur programmes. The adaptive immune system, in which T cells and B cells at the beginning of the In contrast to adaptive immune responses, epigenetic mediate immunological memory, has developed rela- twentieth century as a vaccine reprogramming of transcriptional pathways — rather tively recently in vertebrates (that is, around 500 million to prevent tuberculosis (BCG than gene recombination — mediates trained immunity years ago). By contrast, invertebrate species rely solely vaccine), it also induces (FIG. 1). The immunological phenotype of trained immu- on the innate immune system for defence against patho- protective heterologous effects against infections and nity has been proven to last at least 3 months and up to gens and recognition of tissue damage. In vertebrates, on malignancies. 1 year, although heterologous protection against infec- encounter with a threat and activation of particular lym- tions induced by live vaccines can last for up to 5 years14. phocyte clones that recognize specific antigens from the However, even considering this, trained immunity is invading pathogens, de novo rearrangement of immu- generally reversible and shorter lived than classical noglobulin and T cell receptor gene segments occurs. epitope- specific adaptive immunological memory12,15. This ‘on demand’ production of novel and diverse Importantly however, recent studies have suggested receptors forms the basis for lymphocyte- mediated spe- cific immune memory responses in jawed vertebrates (the gnathostomes)18. An alternative adaptive immune Author addresses system evolved in jawless vertebrates, in which specific 1Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud lymphocyte- mediated immune memory is mediated by University Medical Center, Nijmegen, Netherlands. variable lymphocyte receptors generated via the somatic 2Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, rearrangement of gene elements encoding leucine-rich Nijmegen, Netherlands. repeat motifs19. Both immunoglobulin- based and vari- 3 Department of Genomics and Immunoregulation, Life and Medical Sciences Institute, able lymphocyte receptor-based adaptive immune pro- University of Bonn, Bonn, Germany. cesses in highly differentiated immune cells (that is, 4Department of Genetics, CHU Sainte- Justine Research Centre, Montreal, QC, Canada. memory T cells and B cells or gnathostome lympho- 5Department of Pediatrics, University of Montreal, Montreal, QC, Canada. 6Genetics Section, Department of Medicine, The University of Chicago, Chicago, IL, USA. cytes) induce a recall immune response to the previously 7Institute for Clinical Chemistry and Laboratory Medicine, University Hospital and encountered pathogen that is both stronger and highly Faculty of Medicine Carl Gustav Carus of TU Dresden, Dresden, Germany. specific to the pathogen, ensuring improved survival of 8Centre for Cardiovascular Science, Queen’s Medical Research Institute, University of the organism. Edinburgh, Edinburgh, UK. Given the evolutionary success of organisms lacking 9Meakins- Christie Laboratories, Department of Medicine, McGill University Health adaptive immune responses, which represent up to 97% Centre, Montreal, QC, Canada. of the total biodiversity on Earth20, it is unlikely that 10 Department of Microbiology and Immunology, McGill University, Montreal, QC, Canada. immunological memory has evolved only in vertebrates. 11 McGill International TB Centre, McGill University Health Centre, Montreal, QC, Canada. Indeed, over the past two decades, an increasing num- 12Howard Hughes Medical Institute, Robin Chemers Laboratory of Mammalian Cell ber of studies have provided evidence that the immune Biology and Development, The Rockefeller University, New York, NY, USA. 13Division of Chemical and Systems Biology, Department of Integrative Biomedical system of plants and invertebrates may be