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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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References

  1. Medzhitov, R. & Janeway, C. Innate immune recognition: mechanisms and pathways. Immunol. Rev. 173, 89–97 (2000).

    Article  CAS  PubMed  Google Scholar 

  2. Lanier, L. L. NK cell recognition. Annu. Rev. Immunol. 23, 225–274 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Bonilla, F. A. & Oettgen, H. C. Adaptive immunity. J. Allergy Clin. Immunol. 125, S33–S40 (2010).

    Article  PubMed  Google Scholar 

  4. Bowdish, D. M. E., Loffredo, M. S., Mukhopadhyay, S., Mantovani, A. & Gordon, S. Macrophage receptors implicated in the “adaptive” form of innate immunity. Microbes Infect. 9, 1680–1687 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Netea, M. G., Quintin, J. & Van Der Meer, J. W. M. Trained immunity: a memory for innate host defense. Cell Host Microbe 9, 355–361 (2011). This article describes the memory features of the innate immune system and proposes the term ‘trained immunity’ for the first time.

    Article  CAS  PubMed  Google Scholar 

  6. Naik, S. et al. Inflammatory memory sensitizes skin epithelial stem cells to tissue damage. Nature 550, 475–480 (2017). This study shows that epithelial stem cells maintain chromosomal accessibility at key stress response genes that are activated by the primary stimulus.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Lay, K. et al. Stem cells repurpose proliferation to contain a breach in their niche barrier. eLife 7, e41661 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Christ, A. et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell 172, 162–175 (2018). This study found that a high-fat diet induces long-lasting functional reprogramming of immunity in myeloid cells that remains after mice are returned to a chow diet.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Kurtz, J. Specific memory within innate immune systems. Trends Immunol. 26, 186–192 (2005).

    Article  CAS  PubMed  Google Scholar 

  10. Conrath, U., Beckers, G. J. M., Langenbach, C. J. G. & Jaskiewicz, M. R. Priming for enhanced defense. Annu. Rev. Phytopathol. 53, 97–119 (2015).

    Article  CAS  PubMed  Google Scholar 

  11. Gourbal, B. et al. Innate immune memory: an evolutionary perspective. Immunol. Rev. 283, 21–40 (2018).

    Article  CAS  PubMed  Google Scholar 

  12. Netea, M. G. et al. Trained immunity: a program of innate immune memory in health and disease. Science 352, aaf1098 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Novakovic, B. et al. β-glucan reverses the epigenetic state of lps-induced immunological tolerance. Cell 167, 1354–1368.e14 (2016). This study details the epigenetic and transcriptional landscape of human macrophage LPS-induced tolerance and characterizes the potential of β-glucan to reverse it.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Nankabirwa, V. et al. Child survival and BCG vaccination: a community based prospective cohort study in Uganda. BMC Public Health 15, 175 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  15. Dominguez-Andres, J. & Netea, M. G. Long-term reprogramming of the innate immune system. J. Leukoc. Biol. 105, 329–338 (2018).

    Article  PubMed  CAS  Google Scholar 

  16. Berendsen, M. L. T. et al. Maternal priming: bacillus Calmette-Guérin (BCG) vaccine scarring in mothers enhances the survival of their child with a BCG vaccine scar. J. Pediatric Infect. Dis. Soc. https://doi.org/10.1093/jpids/piy142 (2019).

    Article  Google Scholar 

  17. Moore, R. S., Kaletsky, R. & Murphy, C. T. Piwi/PRG-1 argonaute and TGF-β mediate transgenerational learned pathogenic avoidance. Cell 177, 1827–1841 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Hirano, M., Das, S., Guo, P. & Cooper, M. D. The evolution of adaptive immunity in vertebrates. in. Adv. Immunol. 109, 125–157 (2011).

    Article  CAS  PubMed  Google Scholar 

  19. Cooper, M. D. & Alder, M. N. The evolution of adaptive immune systems. Cell 124, 815–822 (2006).

    Article  CAS  PubMed  Google Scholar 

  20. Purvis, A. & Hector, A. Getting the measure of biodiversity. Nature 405, 212–219 (2000).

    Article  CAS  PubMed  Google Scholar 

  21. Milutinović, B. & Kurtz, J. Immune memory in invertebrates. Semin. Immunol. 28, 328–342 (2016).

    Article  PubMed  CAS  Google Scholar 

  22. Reimer-Michalski, E.-M. & Conrath, U. Innate immune memory in plants. Semin. Immunol. 28, 319–327 (2016).

    Article  CAS  PubMed  Google Scholar 

  23. Kleinnijenhuis, J. et al. Bacille Calmette-Guerin induces NOD2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes. Proc. Natl Acad. Sci. USA 109, 17537–17542 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Di Luzio, N. R. & Williams, D. L. Protective effect of glucan against systemic Staphylococcus aureus septicemia in normal and leukemic mice. Infect. Immun. 20, 804–810 (1978).

    Article  PubMed  PubMed Central  Google Scholar 

  25. Marakalala, M. J. et al. Dectin-1 plays a redundant role in the immunomodulatory activities of β-glucan-rich ligands in vivo. Microbes Infect. 15, 511–515 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Krahenbuhl, J. L., Sharma, S. D., Ferraresi, R. W. & Remington, J. S. Effects of muramyl dipeptide treatment on resistance to infection with Toxoplasma gondii in mice. Infect. Immun. 31, 716–722 (1981).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ribes, S. et al. Intraperitoneal prophylaxis with CpG oligodeoxynucleotides protects neutropenic mice against intracerebral Escherichia coli K1 infection. J. Neuroinflammation 11, 14 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Muñoz, N. et al. Mucosal administration of flagellin protects mice from Streptococcus pneumoniae lung infection. Infect. Immun. 78, 4226–4233 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Zhang, B. et al. Viral infection. Prevention and cure of rotavirus infection via TLR5/NLRC4-mediated production of IL-22 and IL-18. Science 346, 861–865 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. van’t Wout, J. W., Poell, R. & van Furth, R. The role of BCG/PPD-activated macrophages in resistance against systemic candidiasis in mice. Scand. J. Immunol. 36, 713–719 (1992).

    Article  Google Scholar 

  31. Tribouley, J., Tribouley-Duret, J. & Appriou, M. Effect of bacillus Callmette Guerin (BCG) on the receptivity of nude mice to Schistosoma mansoni. C. R. Seances Soc. Biol. Fil. 172, 902–904 (1978).

    CAS  PubMed  Google Scholar 

  32. Kaufmann, E. et al. BCG educates hematopoietic stem cells to generate protective innate immunity against tuberculosis. Cell 172, 176–190.e19 (2018). This article shows that access of BCG to the bone marrow changes the transcriptional landscape of HSCs and multipotent progenitors, leading to local cell expansion and enhanced myelopoiesis.

    Article  CAS  PubMed  Google Scholar 

  33. Bromuro, C. et al. Interplay between protective and inhibitory antibodies dictates the outcome of experimentally disseminated candidiasis in recipients of a Candida albicans vaccine. Infect. Immun. 70, 5462–5470 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Polonelli, L. et al. Therapeutic activity of an engineered synthetic killer antiidiotypic antibody fragment against experimental mucosal and systemic candidiasis. Infect. Immun. 71, 6205–6212 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Bistoni, F. et al. Evidence for macrophage-mediated protection against lethal Candida albicans infection. Infect. Immun. 51, 668–674 (1986).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Bistoni, F. et al. Immunomodulation by a low-virulence, agerminative variant of Candida albicans. Further evidence for macrophage activation as one of the effector mechanisms of nonspecific anti-infectious protection. J. Med. Vet. Mycol. 26, 285–299 (1988).

    Article  CAS  PubMed  Google Scholar 

  37. Quintin, J. et al. Candida albicans infection affords protection against reinfection via functional reprogramming of monocytes. Cell Host Microbe 12, 223–232 (2012).

    Article  CAS  PubMed  Google Scholar 

  38. Vecchiarelli, A. et al. Protective immunity induced by low-virulence Candida albicans: cytokine production in the development of the anti-infectious state. Cell. Immunol. 124, 334–344 (1989).

    Article  CAS  PubMed  Google Scholar 

  39. Tso, G. H. W. et al. Experimental evolution of a fungal pathogen into a gut symbiont. Science 362, 589–595 (2018).

    Article  CAS  PubMed  Google Scholar 

  40. Biering-Sørensen, S. et al. Early BCG-Denmark and neonatal mortality among infants weighing <2500 g: a randomized controlled trial. Clin. Infect. Dis. 65, 1183–1190 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Rieckmann, A. et al. Vaccinations against smallpox and tuberculosis are associated with better long-term survival: a Danish case-cohort study 1971–2010. Int. J. Epidemiol. 46, 695–705 (2017). This study finds that vaccinia and BCG vaccinations are associated with greater long-term survival, which is not explained by the pathogen-specific immune protection that these vaccines offer.

    PubMed  Google Scholar 

  42. Aaby, P. et al. Vaccinia scars associated with better survival for adults. An observational study from Guinea-Bissau. Vaccine 24, 5718–5725 (2006).

    Article  PubMed  Google Scholar 

  43. Aaby, P. et al. Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? J. Infect. Dis. 204, 245–252 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Aaby, P. et al. Non-specific beneficial effect of measles immunisation: analysis of mortality studies from developing countries. BMJ 311, 481–485 (1995). This study reports that the standard-titre measles vaccine may confer a beneficial effect that is unrelated to specific protection against measles infection.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Aaby, P. et al. Non-specific effects of standard measles vaccine at 4.5 and 9 months of age on childhood mortality: randomised controlled trial. BMJ 341, c6495 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Lund, N. et al. The effect of oral polio vaccine at birth on infant mortality: a randomized trial. Clin. Infect. Dis. 61, 1504–1511 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  47. Andersen, A. et al. National immunization campaigns with oral polio vaccine reduce all-cause mortality: a natural experiment within seven randomized trials. Front. Public Health 6, 13 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  48. Benn, C. S., Netea, M. G., Selin, L. K. & Aaby, P. A small jab - a big effect: nonspecific immunomodulation by vaccines. Trends Immunol. 34, 431–439 (2013).

    Article  CAS  PubMed  Google Scholar 

  49. Kleinnijenhuis, J. et al. BCG-induced trained immunity in NK cells: role for non-specific protection to infection. Clin. Immunol. 155, 213–219 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Jensen, K. J. et al. Heterologous immunological effects of early BCG vaccination in low-birth-weight infants in Guinea-Bissau: a randomized-controlled trial. J. Infect. Dis. 211, 956–967 (2015).

    Article  CAS  PubMed  Google Scholar 

  51. Freyne, B. et al. Neonatal BCG vaccination influences cytokine responses to toll-like receptor ligands and heterologous antigens. J. Infect. Dis. 217, 1798–1808 (2018).

    Article  CAS  PubMed  Google Scholar 

  52. Aaby, P. et al. Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies. Lancet 361, 2183–2188 (2003).

    Article  PubMed  Google Scholar 

  53. Blok, B. A. et al. Interacting non-specific immunological effects of BCG and TDAPF vaccinations: an explorative randomized trial. Clin. Infect. Dis. 70, 455–463 (2019).

    Google Scholar 

  54. Arts, R. J. W. et al. BCG vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained immunity. Cell Host Microbe 23, 89–100 (2018).

    Article  CAS  PubMed  Google Scholar 

  55. Walk, J. et al. Outcomes of controlled human malaria infection after BCG vaccination. Nat. Commun. 10, 874 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  56. McCall, M. B. B. et al. Plasmodium falciparum infection causes proinflammatory priming of human TLR responses. J. Immunol. 179, 162–171 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Ataide, M. A. et al. Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog. 10, e1003885 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Fitzgerald, K. A. et al. Cutting edge: Plasmodium falciparum induces trained innate immunity. J. Immunol. 6, 1243–1248 (2018).

    Google Scholar 

  59. Redelman-Sidi, G., Glickman, M. S. & Bochner, B. H. The mechanism of action of BCG therapy for bladder cancer—a current perspective. Nat. Rev. Urol. 11, 153–162 (2014).

    Article  CAS  PubMed  Google Scholar 

  60. Stewart, J. H. & Levine, E. A. Role of bacillus Calmette-Guérin in the treatment of advanced melanoma. Expert. Rev. Anticancer. Ther. 11, 1671–1676 (2011).

    Article  PubMed  Google Scholar 

  61. Powles, R. L. et al. Maintenance of remission in acute myelogenous leukaemia by a mixture of B.C.G. and irradiated leukaemia cells. Lancet 2, 1107–1110 (1977).

    Article  CAS  PubMed  Google Scholar 

  62. Villumsen, M. et al. Risk of lymphoma and leukaemia after bacille Calmette-Guérin and smallpox vaccination: a Danish case-cohort study. Vaccine 27, 6950–6958 (2009).

    Article  PubMed  Google Scholar 

  63. Buffen, K. et al. Autophagy controls BCG-induced trained immunity and the response to intravesical BCG therapy for bladder cancer. PLoS Pathog. 10, e1004485 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Foster, S. L., Hargreaves, D. C. & Medzhitov, R. Gene-specific control of inflammation by TLR-induced chromatin modifications. Nature 447, 972–978 (2007).

    Article  CAS  PubMed  Google Scholar 

  65. Saeed, S. et al. Epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity. Science 345, 1251086 (2014). This article shows that modification of the epigenetic landscape is behind the effects of trained immunity in human monocytes.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  66. Chen, F. et al. Neutrophils prime a long-lived effector macrophage phenotype that mediates accelerated helminth expulsion. Nat. Immunol. 15, 938–946 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hole, C. R. et al. Induction of memory-like dendritic cell responses in vivo. Nat. Commun. 10, 2955 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. Barton, E. S. et al. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447, 326–329 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Sun, J. C. et al. Proinflammatory cytokine signaling required for the generation of natural killer cell memory. J. Exp. Med. 209, 947–954 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Björkström, N. K. et al. Rapid expansion and long-term persistence of elevated NK cell numbers in humans infected with hantavirus. J. Exp. Med. 208, 13–21 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Della Chiesa, M. et al. Phenotypic and functional heterogeneity of human NK cells developing after umbilical cord blood transplantation: a role for human cytomegalovirus? Blood 119, 399–410 (2012).

    Article  PubMed  CAS  Google Scholar 

  73. Foley, B. et al. Human cytomegalovirus (CMV)-induced memory-like NKG2C+ NK cells are transplantable and expand in vivo in response to recipient CMV antigen. J. Immunol. 189, 5082–5088 (2012).

    Article  CAS  PubMed  Google Scholar 

  74. Arase, H., Mocarski, E. S., Campbell, A. E., Hill, A. B. & Lanier, L. L. Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 296, 1323–1326 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Brown, M. G. et al. Vital involvement of a natural killer cell activation receptor in resistance to viral infection. Science 292, 934–937 (2001).

    Article  CAS  PubMed  Google Scholar 

  76. Adams, N. M. et al. Cytomegalovirus infection drives avidity selection of natural killer cells. Immunity 50, 1381–1390.e5 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Grassmann, S. et al. Distinct surface expression of activating receptor Ly49H drives differential expansion of NK cell clones upon murine cytomegalovirus infection. Immunity 50, 1391–1400.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  78. Sun, J. C. & Lanier, L. L. NK cell development, homeostasis and function: parallels with CD8+ T cells. Nat. Rev. Immunol. 11, 645–657 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Min-Oo, G. & Lanier, L. L. Cytomegalovirus generates long-lived antigen-specific NK cells with diminished bystander activation to heterologous infection. J. Exp. Med. 211, 2669–2680 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Rölle, A. et al. IL-12–producing monocytes and HLA-E control HCMV-driven NKG2C+ NK cell expansion. J. Clin. Invest. 124, 5305–5316 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  81. Hammer, Q. et al. Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat. Immunol. 19, 453–463 (2018).

    Article  CAS  PubMed  Google Scholar 

  82. Karo, J. M., Schatz, D. G. & Sun, J. C. The RAG recombinase dictates functional heterogeneity and cellular fitness in natural killer cells. Cell 159, 94–107 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Vivier, E. et al. Innate or adaptive immunity? The example of natural killer cells. Science 331, 44–49 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cooper, M. A. et al. Cytokine-induced memory-like natural killer cells. Proc. Natl Acad. Sci. USA 106, 1915–1919 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Romee, R. et al. Cytokine activation induces human memory-like NK cells. Blood 120, 4751–4760 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Romee, R. et al. Cytokine-induced memory-like natural killer cells exhibit enhanced responses against myeloid leukemia. Sci. Transl Med. 8, 357ra123 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  87. Madera, S. et al. Type I IFN promotes NK cell expansion during viral infection by protecting NK cells against fratricide. J. Exp. Med. 213, 225–233 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Madera, S. & Sun, J. C. Cutting edge: stage-specific requirement of IL-18 for antiviral NK cell expansion. J. Immunol. 194, 1408–1412 (2015).

    Article  CAS  PubMed  Google Scholar 

  89. Nabekura, T., Girard, J.-P. & Lanier, L. L. IL-33 receptor ST2 amplifies the expansion of NK cells and enhances host defense during mouse cytomegalovirus infection. J. Immunol. 194, 5948–5952 (2015).

    Article  CAS  PubMed  Google Scholar 

  90. Weizman, O.-E. et al. Mouse cytomegalovirus-experienced ILC1s acquire a memory response dependent on the viral glycoprotein m12. Nat. Immunol. 20, 1004–1011 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Martinez-Gonzalez, I. et al. Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance allergic lung inflammation. Immunity 45, 198–208 (2016).

    Article  CAS  PubMed  Google Scholar 

  92. Paust, S. et al. Critical role for the chemokine receptor CXCR6 in NK cell–mediated antigen-specific memory of haptens and viruses. Nat. Immunol. 11, 1127–1135 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Gamliel, M. et al. Trained memory of human uterine NK cells enhances their function in subsequent pregnancies. Immunity 48, 951–962 (2018). This study finds that uterine NK cells adapt to pregnancy and can better support subsequent pregnancies.

    Article  CAS  PubMed  Google Scholar 

  94. Gonzales, K. A. U. & Fuchs, E. Skin and its regenerative powers: an alliance between stem cells and their niche. Dev. Cell 43, 387–401 (2017).

    Article  CAS  PubMed  Google Scholar 

  95. Naik, S., Larsen, S. B., Cowley, C. J. & Fuchs, E. Two to tango: dialog between immunity and stem cells in health and disease. Cell 175, 908–920 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Biton, M. et al. T helper cell cytokines modulate intestinal stem cell renewal and differentiation. Cell 175, 1307–1320 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lindemans, C. A. et al. Interleukin-22 promotes intestinal-stem-cell-mediated epithelial regeneration. Nature 528, 560–564 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. von Moltke, J., Ji, M., Liang, H.-E. & Locksley, R. M. Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit. Nature 529, 221–225 (2016).

    Article  CAS  Google Scholar 

  99. Kamada, R. et al. Interferon stimulation creates chromatin marks and establishes transcriptional memory. Proc. Natl Acad. Sci. USA 115, E9162–E9171 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Merad, M., Sathe, P., Helft, J., Miller, J. & Mortha, A. The dendritic cell lineage: ontogeny and function of dendritic cells and their subsets in the steady state and the inflamed setting. Annu. Rev. Immunol. 31, 563–604 (2013).

    Article  CAS  PubMed  Google Scholar 

  101. Yona, S. et al. Fate mapping reveals origins and dynamics of monocytes and tissue macrophages under homeostasis. Immunity 38, 79–91 (2013).

    Article  CAS  PubMed  Google Scholar 

  102. Patel, A. A. et al. The fate and lifespan of human monocyte subsets in steady state and systemic inflammation. J. Exp. Med. 214, 1913–1923 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chavakis, T., Mitroulis, I. & Hajishengallis, G. Hematopoietic progenitor cells as integrative hubs for adaptation to and fine-tuning of inflammation. Nat. Immunol. 20, 802–811 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Mitroulis, I. et al. Modulation of myelopoiesis progenitors is an integral component of trained immunity. Cell 172, 147–161 (2018). This study shows that the induction of trained immunity modulates metabolism of haematopoietic progenitors in the bone marrow and increases myelopoiesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Ordovas-Montanes, J. et al. Allergic inflammatory memory in human respiratory epithelial progenitor cells. Nature 560, 649–654 (2018). This article shows that epithelial stem cells contribute to the persistence of human disease by serving as repositories for allergic memories.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Machiels, B. et al. A gammaherpesvirus provides protection against allergic asthma by inducing the replacement of resident alveolar macrophages with regulatory monocytes. Nat. Immunol. 18, 1310–1320 (2017).

    Article  CAS  PubMed  Google Scholar 

  107. Yao, Y. et al. Induction of autonomous memory alveolar macrophages requires T cell help and is critical to trained immunity. Cell 175, 1634–1650.e17 (2018). This study finds that the formation and maintenance of alveolar macrophages showing memory features occurs independently of monocytes or bone marrow progenitors.

    Article  CAS  PubMed  Google Scholar 

  108. Smale, S. T., Tarakhovsky, A. & Natoli, G. Chromatin contributions to the regulation of innate immunity. Annu. Rev. Immunol. 32, 489–511 (2014).

    Article  CAS  PubMed  Google Scholar 

  109. Ghisletti, S. et al. Identification and characterization of enhancers controlling the inflammatory gene expression program in macrophages. Immunity 32, 317–328 (2010).

    Article  CAS  PubMed  Google Scholar 

  110. Fanucchi, S. et al. Immune genes are primed for robust transcription by proximal long noncoding RNAs located in nuclear compartments. Nat. Genet. 51, 138–150 (2019). This study hows that lncRNA-mediated regulation is central to the establishment of trained immunity.

    Article  CAS  PubMed  Google Scholar 

  111. Natoli, G. & Ostuni, R. Adaptation and memory in immune responses. Nat. Immunol. 20, 783–792 (2019).

    Article  CAS  PubMed  Google Scholar 

  112. Luetke-Eversloh, M. et al. Human cytomegalovirus drives epigenetic imprinting of the IFNG locus in NKG2Chi natural killer cells. PLoS Pathog. 10, e1004441 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  113. Lau, C. M. et al. Epigenetic control of innate and adaptive immune memory. Nat. Immunol. 19, 963–972 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rapp, M. et al. Core-binding factor β and Runx transcription factors promote adaptive natural killer cell responses. Sci. Immunol. 2, eaan3796 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  115. Geary, C. D. et al. Non-redundant ISGF3 components promote NK cell survival in an auto-regulatory manner during viral infection. Cell Rep. 24, 1949–1957.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Lam, V. C., Folkersen, L., Aguilar, O. A. & Lanier, L. L. KLF12 regulates mouse NK cell proliferation. J. Immunol. 203, 981–989 (2019).

    Article  CAS  PubMed  Google Scholar 

  117. Adams, N. M. et al. Transcription factor IRF8 orchestrates the adaptive natural killer cell response. Immunity 48, 1172–1182.e6 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Madera, S. et al. Cutting edge: divergent requirement of T-box transcription factors in effector and memory NK cells. J. Immunol. 200, 1977–1981 (2018).

    Article  CAS  PubMed  Google Scholar 

  119. Zawislak, C. L. et al. Stage-specific regulation of natural killer cell homeostasis and response against viral infection by microRNA-155. Proc. Natl Acad. Sci. USA 110, 6967–6972 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Lu, L.-F. et al. A single miRNA-mRNA interaction affects the immune response in a context- and cell-type-specific manner. Immunity 43, 52–64 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. O’Connell, R. M., Chaudhuri, A. A., Rao, D. S. & Baltimore, D. Inositol phosphatase SHIP1 is a primary target of miR-155. Proc. Natl Acad. Sci. USA 106, 7113–7118 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  122. Saz-Leal, P. et al. Targeting SHIP-1 in myeloid cells enhances trained immunity and boosts response to infection. Cell Rep. 25, 1118–1126 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Verma, D. et al. Anti-mycobacterial activity correlates with altered DNA methylation pattern in immune cells from BCG-vaccinated subjects. Sci. Rep. 7, 12305 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Das, J., Verma, D., Gustafsson, M. & Lerm, M. Identification of DNA methylation patterns predisposing for an efficient response to BCG vaccination in healthy BCG-naïve subjects. Epigenetics 14, 589–601 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Penkov, S., Mitroulis, I., Hajishengallis, G. & Chavakis, T. Immunometabolic crosstalk: an ancestral principle of trained immunity? Trends Immunol. 40, 1–11 (2019).

    Article  CAS  PubMed  Google Scholar 

  126. Norata, G. D. et al. The cellular and molecular basis of translational immunometabolism. Immunity 43, 421–434 (2015).

    Article  CAS  PubMed  Google Scholar 

  127. Domínguez-Andrés, J., Joosten, L. A. & Netea, M. G. Induction of innate immune memory: the role of cellular metabolism. Curr. Opin. Immunol. 56, 10–16 (2019).

    Article  PubMed  CAS  Google Scholar 

  128. Donohoe, D. R. & Bultman, S. J. Metaboloepigenetics: interrelationships between energy metabolism and epigenetic control of gene expression. J. Cell. Physiol. 227, 3169–3177 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Cheng, S.-C. et al. mTOR- and HIF-1-mediated aerobic glycolysis as metabolic basis for trained immunity. Science 345, 1250684–1250684 (2014). This study reports that metabolic rewiring of cells is crucial for the induction of trained immunity.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Arts, R. J. W. et al. Immunometabolic pathways in BCG-induced trained immunity. Cell Rep. 17, 2562–2571 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Arts, R. J. W. et al. Glutaminolysis and fumarate accumulation integrate immunometabolic and epigenetic programs in trained immunity. Cell Metab. https://doi.org/10.1016/j.cmet.2016.10.008 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  132. Liu, P.-S. et al. α-Ketoglutarate orchestrates macrophage activation through metabolic and epigenetic reprogramming. Nat. Immunol. 18, 985–994 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Tannahill, G. M. et al. Succinate is an inflammatory signal that induces IL-1β through HIF-1α. Nature 496, 238–242 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Lampropoulou, V. et al. Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab. 24, 158–166 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cordes, T. et al. Immunoresponsive gene 1 and itaconate inhibit succinate dehydrogenase to modulate intracellular succinate levels. J. Biol. Chem. 291, 14274–14284 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Mills, E. L. et al. Itaconate is an anti-inflammatory metabolite that activates Nrf2 via alkylation of KEAP1. Nature 556, 113–117 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Bambouskova, M. et al. Electrophilic properties of itaconate and derivatives regulate the IκBζ–ATF3 inflammatory axis. Nature 556, 501–504 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Dominguez-Andres, J. et al. The itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity. Cell Metab. 29, 211–220 (2018).

    Article  PubMed  CAS  Google Scholar 

  139. Bekkering, S. et al. Metabolic induction of trained immunity through the mevalonate pathway. Cell 172, 135–146.e9 (2018).

    Article  CAS  PubMed  Google Scholar 

  140. Yvan-Charvet, L. et al. ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation. Science 328, 1689–1693 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Murphy, A. J. et al. ApoE regulates hematopoietic stem cell proliferation, monocytosis, and monocyte accumulation in atherosclerotic lesions in mice. J. Clin. Invest. 121, 4138–4149 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Christ, A. & Latz, E. The Western lifestyle has lasting effects on metaflammation. Nat. Rev. Immunol. 19, 267–268 (2019).

    Article  CAS  PubMed  Google Scholar 

  143. Musher, D. M., Abers, M. S. & Corrales-Medina, V. F. Acute infection and myocardial infarction. N. Engl. J. Med. 380, 171–176 (2019).

    Article  CAS  PubMed  Google Scholar 

  144. Leentjens, J. et al. Trained innate immunity as a novel mechanism linking infection and the development of atherosclerosis. Circ. Res. 122, 664–669 (2018).

    Article  CAS  PubMed  Google Scholar 

  145. Bekkering, S. et al. Oxidized low-density lipoprotein induces long-term proinflammatory cytokine production and foam cell formation via epigenetic reprogramming of monocytes. Arterioscler. Thromb. Vasc. Biol. 34, 1731–1738 (2014).

    Article  CAS  PubMed  Google Scholar 

  146. Braza, M. S. et al. Inhibiting inflammation with myeloid cell-specific nanobiologics promotes organ transplant acceptance. Immunity 49, 819–828 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. van der Valk, F. M. et al. Oxidized phospholipids on lipoprotein(a) elicit arterial wall inflammation and an inflammatory monocyte response in humans. Circulation 134, 611–624 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Bekkering, S. et al. Treatment with statins does not revert trained immunity in patients with familial hypercholesterolemia. Cell Metab. 30, 1–2 (2019).

    Article  CAS  PubMed  Google Scholar 

  149. Bekkering, S. et al. Innate immune cell activation and epigenetic remodeling in symptomatic and asymptomatic atherosclerosis in humans in vivo. Atherosclerosis 254, 228–236 (2016).

    Article  CAS  PubMed  Google Scholar 

  150. Shirai, T. et al. The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease. J. Exp. Med. 213, 337–354 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Zimmermann, P., Finn, A. & Curtis, N. Does BCG vaccination protect against nontuberculous mycobacterial infection? A systematic review and meta-analysis. J. Infect. Dis. 218, 679–687 (2018).

    Article  CAS  PubMed  Google Scholar 

  152. Leentjens, J. et al. BCG vaccination enhances the immunogenicity of subsequent influenza vaccination in healthy volunteers: a randomized, placebo-controlled pilot study. J. Infect. Dis. 212, 1930–1938 (2015).

    Article  CAS  PubMed  Google Scholar 

  153. Ransohoff, R. M. How neuroinflammation contributes to neurodegeneration. Science 353, 777–783 (2016).

    Article  CAS  PubMed  Google Scholar 

  154. Wendeln, A.-C. et al. Innate immune memory in the brain shapes neurological disease hallmarks. Nature 556, 332–338 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Frost, P. S. et al. Neonatal infection leads to increased susceptibility to Aβ oligomer-induced brain inflammation, synapse loss and cognitive impairment in mice. Cell Death Dis. 10, 323 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Low, A., Mak, E., Rowe, J. B., Markus, H. S. & O’Brien, J. T. Inflammation and cerebral small vessel disease: a systematic review. Ageing Res. Rev. 53, 100916 (2019).

    Article  CAS  PubMed  Google Scholar 

  157. Noz, M. P. et al. Trained immunity characteristics are associated with progressive cerebral small vessel disease. Stroke 49, 2910–2917 (2018).

    Article  PubMed  Google Scholar 

  158. Franceschi, C. et al. Immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity. Front. Immunol. 8, 982 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  159. Qian, F. et al. Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly. Aging Cell 11, 104–110 (2012).

    Article  CAS  PubMed  Google Scholar 

  160. Metcalf, T. U. et al. Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors. Aging Cell 14, 421–432 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Hoogeboom, R. et al. A mutated B cell chronic lymphocytic leukemia subset that recognizes and responds to fungi. J. Exp. Med. 210, 59–70 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Jurado-Camino, T. et al. Chronic lymphocytic leukemia: a paradigm of innate immune cross-tolerance. J. Immunol. 194, 719–727 (2015).

    Article  CAS  PubMed  Google Scholar 

  163. Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Lee, S. H. et al. TNFα enhances cancer stem cell-like phenotype via Notch-Hes1 activation in oral squamous cell carcinoma cells. Biochem. Biophys. Res. Commun. 424, 58–64 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Hodge, D. R., Hurt, E. M. & Farrar, W. L. The role of IL-6 and STAT3 in inflammation and cancer. Eur. J. Cancer 41, 2502–2512 (2005).

    Article  CAS  PubMed  Google Scholar 

  166. Rabold, K., Netea, M. G., Adema, G. J. & Netea-Maier, R. T. Cellular metabolism of tumor-associated macrophages - functional impact and consequences. FEBS Lett. 591, 3022–3041 (2017).

    Article  CAS  PubMed  Google Scholar 

  167. Cubas, P., Vincent, C. & Coen, E. An epigenetic mutation responsible for natural variation in floral symmetry. Nature 401, 157–161 (1999).

    Article  CAS  PubMed  Google Scholar 

  168. Greer, E. L. et al. A histone methylation network regulates transgenerational epigenetic memory in C. elegans. Cell Rep. 7, 113–126 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Tate, A. T., Andolfatto, P., Demuth, J. P. & Graham, A. L. The within-host dynamics of infection in trans-generationally primed flour beetles. Mol. Ecol. 26, 3794–3807 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. No Authors Listed. Meeting of the Strategic Advisory Group of Experts on immunization, April 2014 - conclusions and recommendations. Wkly Epidemiol. Rec. 89, 221–236 (2014).

    Google Scholar 

  171. Shann, F. The heterologous (non-specific) effects of vaccines: implications for policy in high-mortality countries. Trans. R. Soc. Trop. Med. Hyg. 109, 5–8 (2015).

    Article  CAS  PubMed  Google Scholar 

  172. Benn, C. S., Fisker, A. B., Whittle, H. C. & Aaby, P. Revaccination with live attenuated vaccines confer additional beneficial nonspecific effects on overall survival: a review. EBioMedicine 10, 312–317 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Locht, C. & Mielcarek, N. Live attenuated vaccines against pertussis. Expert. Rev. Vaccines 13, 1147–1158 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Meyers, P. A. et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival-a report from the Children’s Oncology Group. J. Clin. Oncol. 26, 633–638 (2008).

    Article  CAS  PubMed  Google Scholar 

  175. Muramatsu, D. et al. β-glucan derived from Aureobasidium pullulans is effective for the prevention of influenza in mice. PLoS One 7, e41399 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Mulder, W. J. M., Ochando, J., Joosten, L. A. B., Fayad, Z. A. & Netea, M. G. Therapeutic targeting of trained immunity. Nat. Rev. Drug. Discov. 18, 553–566 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Levine, D. B. The Hospital for the Ruptured and Crippled: William Bradley Coley, third Surgeon-in-Chief 1925-1933. HSS J. 4, 1–9 (2008).

    Article  PubMed  Google Scholar 

  178. Coley, W. B. II. Contribution to the knowledge of sarcoma. Ann. Surg. 14, 199–220 (1891).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Old, L. J., Clarke, D. A. & Benacerraf, B. Effect of bacillus Calmette-Guérin infection on transplanted tumours in the mouse. Nature 184, 291–292 (1959).

    Article  PubMed  Google Scholar 

  180. Ostadrahimi, A. et al. Effect of beta glucan on white blood cell counts and serum levels of IL-4 and IL-12 in women with breast cancer undergoing chemotherapy: a randomized double-blind placebo-controlled clinical trial. Asian Pac. J. Cancer Prev. 15, 5733–5739 (2014).

    Article  PubMed  Google Scholar 

  181. Bashir, K. M. I. & Choi, J.-S. Clinical and physiological perspectives of β-glucans: the past, present, and future. Int. J. Mol. Sci. 18, 1906 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  182. Vetvicka, V., Vannucci, L., Sima, P. & Richter, J. Beta glucan: supplement or drug? from laboratory to clinical trials. Molecules 24, 1251 (2019).

    Article  PubMed Central  CAS  Google Scholar 

  183. Lim, W. A. & June, C. H. The principles of engineering immune cells to treat. Cancer Cell 168, 724–740 (2017).

    CAS  Google Scholar 

  184. Sharma, P. & Allison, J. P. The future of immune checkpoint therapy. Science 348, 56–61 (2015).

    Article  CAS  PubMed  Google Scholar 

  185. Routy, B. et al. The gut microbiota influences anticancer immunosurveillance and general health. Nat. Rev. Clin. Oncol. 15, 382–396 (2018).

    Article  CAS  PubMed  Google Scholar 

  186. Lameijer, M. et al. Efficacy and safety assessment of a TRAF6-targeted nanoimmunotherapy in atherosclerotic mice and non-human primates. Nat. Biomed. Eng. 2, 279–292 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Netea, M. G., Schlitzer, A., Placek, K., Joosten, L. A. B. & Schultze, J. L. Innate and adaptive immune memory: an evolutionary continuum in the host’s response to pathogens. Cell Host Microbe 25, 13–26 (2019).

    Article  CAS  PubMed  Google Scholar 

  188. Ridker, P. M. et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N. Engl. J. Med. 377, 1119–1131 (2017).

    Article  CAS  PubMed  Google Scholar 

  189. Domínguez-Andrés, J. et al. Bromodomain inhibitor I-BET151 suppresses immune responses during fungal-immune interaction. Eur. J. Immunol. 49, 2044–2050 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Alqahtani, A. et al. Bromodomain and extra-terminal motif inhibitors: a review of preclinical and clinical advances in cancer therapy. Future Sci. OA 5, FSO372 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

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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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