Mechanisms involved in the transmission of trained immunity to the offspring
Authors: Elisabeth A. Dulfer, Jorge Domínguez-Andrés
Journal: Journal of Allergy and Clinical Immunology (2024)

Despite global efforts, infectious and inflammatory diseases continue to be major causes of mortality, presenting marked disparities in disease burden across different populations with significant differences in susceptibility and severity. The concept of "trained immunity" (abbreviated here as TRIM) provides a compelling framework to decipher these complex epidemiologic patterns. TRIM describes how prior exposures mold the innate immune system to respond more robustly to subsequent challenges.1Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Google Scholar This phenomenon, often considered a form of "memory" within the innate immune system, involves functional reprogramming of innate immune cells, driven by metabolic and epigenetic changes. TRIM is particularly significant, as it is hypothesized to underlie the broad protective effects of certain vaccines, such as the bacillus Calmette-Guérin (BCG) vaccine. These effects have been demonstrated in epidemiologic studies and clinical trials to safeguard against a range of pathogens beyond their intended targets. An ongoing scientific debate is focused on whether and how TRIM characteristics can be transmitted to offspring. In addition to the potential involvement of epigenetic inheritance, immune components passed to subsequent generations have the ability to modulate the developing immune system. It is crucial to distinguish this process from passive immunity, wherein transferred immune factors offer specific, targeted protection. Understanding these mechanisms could inform strategies for vaccinations and other interventions aimed at enhancing immune resilience and development in the next generations. From an evolutionary standpoint, insights into how TRIM is transmitted could deepen our understanding of human evolution. Here, we discuss the 3 principal mechanisms through which TRIM may be transmitted (Fig 1) and highlight the potential implications for future research and clinical practice. Epigenetic modifications are pivotal in the functional reprogramming of innate immune cells, affecting circulating cell types such as monocytes and natural killer cells, which collectively are termed peripheral TRIM.1Netea M.G. Domínguez-Andrés J. Barreiro L.B. Chavakis T. Divangahi M. Fuchs E. et al.Defining trained immunity and its role in health and disease.Nat Rev Immunol. 2020; 20: 375-388Google Scholar These modifications are also notable within the bone marrow, influencing progenitor cells and their descendants, which we refer to as "central TRIM." Among the epigenetic changes, methylation is a well-studied marker. Identified signatures such as H3K4me1, H3K4me3, and H3K27ac are linked to a TRIM phenotype of innate immune cells, which is characterized by their ability to exhibit an enhanced response to secondary infections following an initial exposure. A critical question in the field is whether these epigenetic changes are transmitted to daughter cells during cell division and further to offspring through gametogenesis and fertilization. Evidence suggests that parental factors, such as infections and dietary changes, modify the DNA methylation patterns in the immune cells of offspring. These observations have been supported by studies in both animals and humans. For instance, there is a correlation between vaccination of parents with BCG and enhanced protection in their vaccinated children.2Berendsen M.L.T. Schaltz-Buchholzer F. Bles P. Biering-Sørensen S. Jensen K.J. Monteiro I. et al.Parental bacillus Calmette-Guérin vaccine scars decrease infant mortality in the first six weeks of life: a retrospective cohort study.EClinicalMedicine. 2021; 39101049Google Scholar The results of a study inducing sepsis in mice also supported the idea of transgenerational inheritance of immune traits through epigenetic changes, as the DNA methylation profiles of survivors' sperm cells were altered compared with those of controls.3Bomans K. Schenz J. Tamulyte S. Schaack D. Weigand M.A. Uhle F. Paternal sepsis induces alterations of the sperm methylome and dampens offspring immune responses—an animal study.Clin Epigenetics. 2018; 10: 89Google Scholar Their male descendants exhibited lower proinflammatory cytokine responses following injection of LPS and showed a dampened pulmonary immune response as well. In another study in mice, the use of Candida albicans or zymosan to induce TRIM led to alterations in the sperm methylome, which resulted in enhanced protection patterns. Those persisted through the third generation, along with enhanced protection against heterologous infections,4Katzmarski N. Domínguez-Andrés J. Cirovic B. Renieris G. Ciarlo E. Le Roy D. et al.Transmission of trained immunity and heterologous resistance to infections across generations.Nat Immunol. 2021; 22: 1382-1390Google Scholar although a parallel study using similar conditions did not find the same patterns of transmission.5Kaufmann E. Landekic M. Downey J. Chronopoulos J. Teimouri Nezhad S. Tran K. et al.Lack of evidence for intergenerational inheritance of immune resistance to infections.Nat Immunol. 2022; 23: 203-207Google Scholar The cause of the differences observed remains uncertain; it may be attributed to variations in mouse substrains, housing conditions, diet, microbiome, infection models, or other unidentified factors. In utero exposure to inflammatory conditions significantly influences development and function of the fetal immune system. Soluble mediators, including cytokines and transcription factors, can be transferred from the mother to the offspring during pregnancy or via breast-feeding. These mediators can potentially train the developing immune system. Recent research highlights the potential for maternal immune components to act as training agents for the neonate. For example, a study found that neonates born to mothers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) displayed enhanced cytokine functionality. They exhibited increased cord blood levels of natural killer and γδ T cells that were at least partly neonatally derived.6Gee S. Chandiramani M. Seow J. Pollock E. Modestini C. Das A. et al.The legacy of maternal SARS-CoV-2 infection on the immunology of the neonate.Nat Immunol. 2021; 22: 1490-1502Google Scholar These findings suggest that the inflammatory environment experienced in utero can alter neonatal innate immunity. However, whether these changes represent a direct transmission of TRIM or are simply a byproduct of passive immune transfer remains unclear. Moreover, not all cytokines and regulatory factors can cross the placenta, their transfer being restricted by characteristics such as molecular size, charge, and glycosylation. This limitation can affect the extent and nature of immune training in the fetus. Another study investigating the relationship between maternal immune status and childhood asthma found that maternal metabolites, such as lipids, vitamins, and hormones, are detected by fetal bone marrow progenitors.7DeVries A. McCauley K. Fadrosh D. Fujimura K.E. Stern D.A. Lynch S.V. Vercelli D. Maternal prenatal immunity, neonatal trained immunity, and early airway microbiota shape childhood asthma development.Allergy. 2022; 77: 3617-3628Google Scholar This interaction might contribute to prenatal immune priming, although its exact role in TRIM is yet to be fully understood. Finally, passively transferred maternal antibodies can bind to the Fc receptor on innate immune cells, providing some degree of nonspecific immune activation. Whether this process constitutes TRIM is debatable, however, as it likely does not involve the long-term functional reprogramming of the offspring's innate immune cells. The microbiome plays a critical role in both the development and function of the immune system. Gut bacteria produce metabolites such as short-chain fatty acids with immunomodulatory properties that influence the TRIM response, notably following BCG vaccination.8Stražar M. Mourits V.P. Koeken V. de Bree L.C.J. Moorlag S. Joosten L.A.B. et al.The influence of the gut microbiome on BCG-induced trained immunity.Genome Biol. 2021; 22: 275Google Scholar Additionally, microbial products can interact with immune cells directly by activating pattern recognition receptors and affecting epigenetic modifications, thereby altering immune responses. The vertical transmission of maternal microbiota can significantly influence the immune system in the neonate, resulting in changes in intestinal transcription profiles and an altered inflammatory response to invading microbes.9Gomez de Agüero M. Ganal-Vonarburg S.C. Fuhrer T. Rupp S. Uchimura Y. Li H. et al.The maternal microbiota drives early postnatal innate immune development.Science. 2016; 351: 1296-1302Google Scholar Breast-feeding serves as a crucial conduit for transferring maternal microbiota to the infant, potentially extending the influence of maternally induced immunologic changes beyond birth. Maternal microbiota can also initiate a cascade of immunologic events, influencing the immune system of progeny in an indirect manner. One example is modulation of the homeostatic control governing the proportion of RORγ+ regulatory T cells within the gut, which is shaped by the maternal microbial environment. As demonstrated in murine models, this control of variations in frequencies of RORγ+ regulatory T cells is determined maternally and wields a direct impact on infection outcomes and susceptibility to autoimmune diseases in subsequent generations. Additionally, it has been observed that gut epithelial stem cells can undergo modifications in response to a mild infection during prenatal development, showing increased expression of genes associated with antigen presentation and antimicrobial peptides. The impact of this transient maternal infection appears to be tissue specific and mediated principally by IL-6.10Lim A.I. McFadden T. Link V.M. Han S.J. Karlsson R.M. Stacy A. et al.Prenatal maternal infection promotes tissue-specific immunity and inflammation in offspring.Science. 2021; 373eabf3002Google Scholar Much like the maternal transfer of immune components discussed earlier, the mechanism by which microbiota influence immunity in progeny relates more to priming of the induction of TRIM rather than to transmission of a TRIM phenotype outright. This distinction underscores the nuanced ways in which maternal factors can shape the immune landscape of the next generation. Accumulating evidence supports the transgenerational inheritance of innate immune traits in mammals, yet the precise mechanisms remain largely undefined. Key questions persist about the duration and impact of inherited TRIM, the influence of parental exposures, and the optimal targets for intervention. Clarifying these factors will enhance our approach to disease prevention and vaccine efficacy. Future research integrating epidemiologic cohort findings with actual immunologic correlates is essential to fully understand the involved immunologic changes. This exploration is crucial not only for advancing vaccine development, such as by improving efficacy for vulnerable populations, but also for its potential to reshape public health strategies. Ultimately, this line of inquiry holds promise for improving global health outcomes and deepening our understanding of human adaptation across generations. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest.