Immunological memory is an important evolutionary trait that improves host survival upon reinfection. Memory is a characteristic recognized within both the innate and adaptive arms of the immune ...system. Although the mechanisms and properties through which innate and adaptive immune memory are induced are distinct, they collude to improve host defense to pathogens. Here, we propose that innate immune memory, or “trained immunity,” is a primitive form of adaptation in host defense, resulting from chromatin structure rearrangement, which provides an increased but non-specific response to reinfection. In contrast, adaptive immune memory is more advanced, with increased magnitude of response mediated through epigenetic changes, as well as specificity mediated by gene recombination. An integrative model of immune memory is important for broad understanding of host defense, and for identifying the most effective approaches to modulate it for the benefit of patients with infections and immune-mediated diseases.
In this Perspective, Netea et al. examine the distinct factors involved in innate immune memory (also termed trained immunity) and in the more advanced and specific adaptive immune memory. The authors then propose an integrative model of immune memory for a better understanding of the host defense system.
American tegumentary leishmaniasis is a vector-borne parasitic disease caused by Leishmania protozoans. Innate immune cells undergo long-term functional reprogramming in response to infection or ...Bacillus Calmette-Guérin (BCG) vaccination via a process called trained immunity, conferring non-specific protection from secondary infections. Here, we demonstrate that monocytes trained with the fungal cell wall component β-glucan confer enhanced protection against infections caused by Leishmania braziliensis through the enhanced production of proinflammatory cytokines. Mechanistically, this augmented immunological response is dependent on increased expression of interleukin 32 (IL-32). Studies performed using a humanized IL-32 transgenic mouse highlight the clinical implications of these findings in vivo. This study represents a definitive characterization of the role of IL-32γ in the trained phenotype induced by β-glucan or BCG, the results of which improve our understanding of the molecular mechanisms governing trained immunity and Leishmania infection control.
Display omitted
•Trained immunity induced by β-glucan protects against L. braziliensis infections•β-glucan-induced protection against Leishmania is mediated by IL-32 and IL-1•Bone marrow of IL-32TG mice shows increased responsiveness after β-glucan exposure•IL-32 modulates gene transcription of HSPCs and GMP in BCG-vaccinated subjects
dos Santos et al. describe that trained immunity induced by β-glucan confers protection against L. braziliensis infections. Infection control is associated with IL-32 and IL-1 induction. Genetic variation in the IL-32 gene enhances induction of trained immunity leading to proinflammatory gene transcription in bone marrow hematopoietic stem and progenitor cells.
Trained innate immunity fosters a sustained favorable response of myeloid cells to a secondary challenge, despite their short lifespan in circulation. We thus hypothesized that trained immunity ...acts via modulation of hematopoietic stem and progenitor cells (HSPCs). Administration of β-glucan (prototypical trained-immunity-inducing agonist) to mice induced expansion of progenitors of the myeloid lineage, which was associated with elevated signaling by innate immune mediators, such as IL-1β and granulocyte-macrophage colony-stimulating factor (GM-CSF), and with adaptations in glucose metabolism and cholesterol biosynthesis. The trained-immunity-related increase in myelopoiesis resulted in a beneficial response to secondary LPS challenge and protection from chemotherapy-induced myelosuppression in mice. Therefore, modulation of myeloid progenitors in the bone marrow is an integral component of trained immunity, which to date, was considered to involve functional changes of mature myeloid cells in the periphery.
Display omitted
•Trained immunity (TI) modulates hematopoietic progenitors in bone marrow•TI is associated with adaptations in cell metabolism in progenitors•TI increases expansion of hematopoietic progenitors and myelopoiesis•TI promotes beneficial responses to systemic inflammation and chemotherapy
Modulation of hematopoietic stem and progenitor cells during trained immunity allows a sustained response of myeloid cells to a secondary challenge despite their short lifespan in circulation.
Macrophages are a heterogeneous cell population involved in tissue homeostasis, inflammation, and various pathologies. Although the major tissue-resident macrophage populations have been extensively ...studied, interstitial macrophages (IMs) residing within the tissue parenchyma remain poorly defined. Here we studied IMs from murine lung, fat, heart, and dermis. We identified two independent IM subpopulations that are conserved across tissues: Lyve1
MHCII
CX3CR1
(Lyve1
MHCII
) and Lyve1
MHCII
CX3CR1
(Lyve1
MHCII
) monocyte-derived IMs, with distinct gene expression profiles, phenotypes, functions, and localizations. Using a new mouse model of inducible macrophage depletion (
), we found that the absence of Lyve1
MHCII
IMs exacerbated experimental lung fibrosis. Thus, we demonstrate that two independent populations of IMs coexist across tissues and exhibit conserved niche-dependent functional programming.
Induction of trained immunity by Bacille-Calmette-Guérin (BCG) vaccination mediates beneficial heterologous effects, but the mechanisms underlying its persistence and magnitude remain elusive. In ...this study, we show that BCG vaccination in healthy human volunteers induces a persistent transcriptional program connected to myeloid cell development and function within the hematopoietic stem and progenitor cell (HSPC) compartment in the bone marrow. We identify hepatic nuclear factor (HNF) family members 1a and b as crucial regulators of this transcriptional shift. These findings are corroborated by higher granulocyte numbers in BCG-vaccinated infants, HNF1 SNP variants that correlate with trained immunity, and elevated serum concentrations of the HNF1 target alpha-1 antitrypsin. Additionally, transcriptomic HSPC remodeling was epigenetically conveyed to peripheral CD14+ monocytes, displaying an activated transcriptional signature three months after BCG vaccination. Taken together, transcriptomic, epigenomic, and functional reprogramming of HSPCs and peripheral monocytes is a hallmark of BCG-induced trained immunity in humans.
Display omitted
•Human BCG vaccination induces a persistent innate immune training of CD14+ monocytes•BCG vaccination imprints a persistent transcriptomic myeloid bias on human HSPCs•Hepatic nuclear factors are regulators of BCG-induced trained immunity in HSPCs•BCG induces persistent epigenetic changes in peripheral CD14+ monocytes
Cirovic and de Bree et al. investigate the effects of BCG vaccination in humans and reveal the induction of a transcriptomic rewiring of human stem and progenitor cells toward the myeloid cell lineage, instructed by hepatic nuclear factors, resulting in epigenetic and functional changes within CD14+ peripheral monocytes.
Increasing quantities of atmospheric anthropogenic fixed nitrogen entering the open ocean could account for up to about a third of the ocean's external (nonrecycled) nitrogen supply and up to ∼30% of ...the annual new marine biological production, ∼0.3 petagram of carbon per year. This input could account for the production of up to ∼1.6 teragrams of nitrous oxide ($\text{N}_{2}\text{O}$) per year. Although ∼10% of the ocean's drawdown of atmospheric anthropogenic carbon dioxide may result from this atmospheric nitrogen fertilization, leading to a decrease in radiative forcing, up to about two-thirds of this amount may be offset by the increase in$\text{N}_{2}\text{O}$emissions. The effects of increasing atmospheric nitrogen deposition are expected to continue to grow in the future.
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.
Long-term epigenetic reprogramming of innate immune cells in response to microbes, also termed “trained immunity,” causes prolonged altered cellular functionality to protect from secondary ...infections. Here, we investigated whether sterile triggers of inflammation induce trained immunity and thereby influence innate immune responses. Western diet (WD) feeding of Ldlr−/− mice induced systemic inflammation, which was undetectable in serum soon after mice were shifted back to a chow diet (CD). In contrast, myeloid cell responses toward innate stimuli remained broadly augmented. WD-induced transcriptomic and epigenomic reprogramming of myeloid progenitor cells led to increased proliferation and enhanced innate immune responses. Quantitative trait locus (QTL) analysis in human monocytes trained with oxidized low-density lipoprotein (oxLDL) and stimulated with lipopolysaccharide (LPS) suggested inflammasome-mediated trained immunity. Consistently, Nlrp3−/−/Ldlr−/− mice lacked WD-induced systemic inflammation, myeloid progenitor proliferation, and reprogramming. Hence, NLRP3 mediates trained immunity following WD and could thereby mediate the potentially deleterious effects of trained immunity in inflammatory diseases.
Display omitted
•Western diet triggers innate immunity, NOD-like, and IFN signaling pathways•Western diet alters in vivo LPS responses of GMPs•Western diet induces long-lasting trained immunity in myeloid cells•NLRP3 recognizes Western diet and mediates trained immunity
Systemic inflammation induced by a Western diet is largely blunted by dietary changes, but myeloid cell-induced innate immune responses remain augmented and could potentially contribute to inflammatory disease.
Intergenerational inheritance of immune traits linked to epigenetic modifications has been demonstrated in plants and invertebrates. Here we provide evidence for transmission of trained immunity ...across generations to murine progeny that survived a sublethal systemic infection with Candida albicans or a zymosan challenge. The progeny of trained mice exhibited cellular, developmental, transcriptional and epigenetic changes associated with the bone marrow-resident myeloid effector and progenitor cell compartment. Moreover, the progeny of trained mice showed enhanced responsiveness to endotoxin challenge, alongside improved protection against systemic heterologous Escherichia coli and Listeria monocytogenes infections. Sperm DNA of parental male mice intravenously infected with the fungus C. albicans showed DNA methylation differences linked to immune gene loci. These results provide evidence for inheritance of trained immunity in mammals, enhancing protection against infections.
Today's surface ocean is saturated with respect to calcium carbonate, but increasing atmospheric carbon dioxide concentrations are reducing ocean pH and carbonate ion concentrations, and thus the ...level of calcium carbonate saturation. Experimental evidence suggests that if these trends continue, key marine organisms--such as corals and some plankton--will have difficulty maintaining their external calcium carbonate skeletons. Here we use 13 models of the ocean-carbon cycle to assess calcium carbonate saturation under the IS92a 'business-as-usual' scenario for future emissions of anthropogenic carbon dioxide. In our projections, Southern Ocean surface waters will begin to become undersaturated with respect to aragonite, a metastable form of calcium carbonate, by the year 2050. By 2100, this undersaturation could extend throughout the entire Southern Ocean and into the subarctic Pacific Ocean. When live pteropods were exposed to our predicted level of undersaturation during a two-day shipboard experiment, their aragonite shells showed notable dissolution. Our findings indicate that conditions detrimental to high-latitude ecosystems could develop within decades, not centuries as suggested previously.
PDF
