comment Trained immunity, tolerance, priming and diferentiation: distinct immunological processes The similarities and diferences between trained immunity and other immune processes are the subject of intense interrogation. Therefore, a consensus on the defnition 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 feld of research. Here we aim to establish a common framework that describes the experimental standards for defning trained immunity. Maziar Divangahi, Peter Aaby, Shabaana Abdul Khader, Luis B. Barreiro, Siroon Bekkering, Triantafyllos Chavakis, Reinout van Crevel, Nigel Curtis, Andrew R. DiNardo, Jorge Dominguez-Andres, Raphael Duivenvoorden, Stephanie Fanucchi, Zahi Fayad, Elaine Fuchs, Melanie Hamon, Kate L. Jefrey, Nargis Khan, Leo A. B. Joosten, Eva Kaufmann, Eicke Latz, Giuseppe Matarese, Jos W. M. van der Meer, Musa Mhlanga, Simone J. C. F. M. Moorlag, Willem J. M. Mulder, Shruti Naik, Boris Novakovic, Luke O’Neill, Jordi Ochando, Keiko Ozato, Niels P. Riksen, Robert Sauerwein, Edward R. Sherwood, Andreas Schlitzer, Joachim L. Schultze, Michael H. Sieweke, Christine Stabell Benn, Henk Stunnenberg, Joseph Sun, Frank L. van de Veerdonk, Sebastian Weis, David L. Williams, Ramnik Xavier and Mihai G. Netea rained immunity has been defined bacteria (for example, Bacille Calmette– pathogens. Epidemiological studies have as one form of adaptation of innate Guérin (BCG)), fungi (for example, Candida shown that vaccination with certain live Thost defense mechanisms or a de albicans) or helminth parasites (for example, vaccines provides heterologous protection facto innate immune memory. Following Nippostrongylus brasiliensis) protects against against unrelated pathogens. For example, exposure to particular infectious agents heterologous infections independently of BCG vaccination in newborn children or vaccines, trained immunity can mount adaptive immunity1. provides protection not only against a faster and greater response against a Furthermore, while the rationale tuberculosis but also against respiratory secondary challenge with homologous or underlying the use of adjuvants in vaccine tract infections and neonatal sepsis, even heterologous pathogens1. Trained formulations is to improve the efficacy and it significantly reduces mortality1. immunity has emerged as a focal point in of adaptive immunity, little attention has BCG-induced trained immunity has also immunology research and has added a layer been given to the direct effects of adjuvants been shown to provide protection against of complexity to our previous understanding on innate immunity and early protection experimental models of yellow fever11 of immune memory, that is, a trait limited against infection. For instance, β-glucan and malaria12 infection. Interestingly, the to antigen-specific responses of the adaptive (mainly encountered as a component of anticancer effects of BCG (for example, in immune system. Although more than 95% fungal cell walls that activates dectin-1) bladder cancer) have also been linked to of species (plants and invertebrates) rely enhances resistance to acute infection with trained immunity13. Thus, trained immunity solely on innate immunity for host defense2, Staphylococcus aureus4 or chronic infection is an evolutionary trait that increases immunological memory has been associated with Mycobacterium tuberculosis (Mtb)5. the fitness of plants, invertebrates and mainly with the adaptive arm of the immune Similarly, administration of agonists of vertebrates against pathogenic microbes. response in vertebrates. However, it is highly NOD-like receptors (for example, NOD2) It is also important to emphasize that, unlikely that a critical evolutionary trait or Toll-like receptors (for example, TLR9) although trained immunity improves the like immunological memory is restricted have been shown to provide protection host’s defense against subsequent pathogenic to adaptive immunity and has not evolved against Toxoplasma6 and sepsis caused by threats, it may also be maladaptive in the in the innate arm of immunity in the Escherichia coli7, respectively. Intriguingly, context of chronic inflammatory disease, entire spectrum of living organisms. In the induction of trained immunity is such as atherosclerosis1. Indeed, in addition fact, systemic acquired resistance (SAR) regulated by a unique set of mediators. For to microbial products, trained immunity can is a well-defined state corresponding to instance, BCG-mediated trained immunity also be induced by endogenous atherogenic innate immunological memory in plants3. requires type II interferon (IFN)8, Mtb substances, including oxidized low-density Similarly, the innate immune system of impaired trained immunity via type I IFN9, lipoprotein particles, lipoprotein (a) and invertebrates (for example, mosquitoes, the and the inflammatory cytokines interleukin catecholamines1,14. In animal models of bumble bee Bombus terrestris, snails, and (IL)-1 and GM-CSF were essential for atherosclerosis, a Western-type diet induces so on) has the capacity to generate memory β-glucan-induced trained immunity10. trained immunity, which persists even after a responses to subsequent reinfection with In addition to what has been seen in switch to a healthy chow diet15. Nevertheless, the same or different pathogens1. There is experimental animal models, there is now it is remarkable that trained immunity also compelling evidence in animal models ample evidence that trained immunity is a induced by BCG vaccination has also been that an initial infection or vaccination with component of the human host response to involved in improved induction of immune 2 NATURE IMMUNOLOGY | VOL 22 | JANUARY 2021 | 2–6 | www.nature.com/natureimmunology comment a Differentiation b Priming (HSPCs) in the bone marrow (BM) and in circulating immune cells, and peripherally, at the tissue-specific level. It has been demonstrated that BCG, β-glucan, and a Western-type diet reprogram BM-HSPCs toward myelopoiesis and generate trained immunity8,10,15. These studies provide an explanation for why short-lived innate immune cells can acquire memory with Innate immune response Innate immune response a persistent phenotype in vivo. However, this may also impact the replacement of tissue-resident innate immune cells with Time Time Changed condition 1st insult 2nd insult new and reprogrammed HSPCs. It has been insult shown that, following pulmonary insults, a reduction in yolk-sac-derived alveolar c Trained immunity d Tolerance macrophages is compensated for through the accumulation of BM-derived macrophages in the lung airways17. For example, infection of mice with gammaherpesviruses provided protection against allergic asthma, as it caused resident alveolar macrophages (AMs) to be replaced with BM-derived AMs18. Thus, a new imprinted AM may have a completely different functional capacity to that of an original fetal-derived AM. It Innate immune response Innate immune response has also been shown that the metabolism of AMs is significantly different from that Time Time of bone-marrow-derived macrophages 1st insult 2nd insult 1st insult 2nd insult (BMDMs), the latter being more glycolytic and bactericidal19. In addition, a murine Fig. 1 | Schematic presentation of the behavior of innate immune responses during the different model of pulmonary adenoviral infection adaptive programs induced in innate immune cells. a, Differentiation. b, Priming. c, Trained immunity induces trained immunity in AMs, which (innate immune memory). d, Tolerance. is dependent on T cells but independent of BMDMs20. Furthermore, the inflammatory site may also alter the functional capacity of the local stromal cells that induce regulation and immunological self-tolerance involved in innate memory responses trained immunity in residential innate in models of autoimmunity such as type depend solely on epigenetic remodeling, immune cells. Strikingly, following skin 1 diabetes and multiple sclerosis16. While and trained immunity appears to be devoid inflammation, epithelial stem cells maintain the precise molecular mechanisms are of specificity. It has been proposed that prolonged chromatin accessibility at key still not fully understood, this evidence immune memory in innate and adaptive inflammatory genes. This feature expedites supports the broad rationale that exposure immunity represents an evolutionary and heightens their response to subsequent to microbes may help to antagonize continuum in which a more robust stressors and potentially influences stem conditions sharing chronic inflammation immune response evolved first, mediated cell cross-talk with trained immune cells21. and tissue damage, such as autoimmunity. by epigenetic mechanisms, while specificity Therefore, central and peripheral factors, The beneficial effect of BCG vaccination, at evolved later in a subgroup of species or a combination of both, can impact least in some autoimmune disorders, is an (vertebrates) through gene recombination2. the duration and maintenance of trained interesting facet of host–microbe interplay While some of the mechanisms for immunity. in the pathophysiology and treatment of epigenetic remodeling and metabolic immune-mediated diseases. reprogramming during trained immunity Diferentiation, priming, tolerance and have been recently reviewed1, the duration training Mechanisms of trained immunity and maintenance of chromatin-driven Adaptations in innate immune Immunological memory in the