Bekkering S, DomÃ nguez-AndrÃ©s J, Joosten LAB, Riksen NP, Netea MG. Trained Immunity Reprogramming Innate Immunity in Health and Disease

Annual Review of Immunology
Trained Immunity:
Reprogramming Innate
Immunity in Health
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and Disease
Annu. Rev. Immunol. 2021.39:667-693. Downloaded from www.annualreviews.org
Siroon Bekkering,1 Jorge Domínguez-Andrés,1

Leo A.B. Joosten,1,2 Niels P. Riksen,1
and Mihai G. Netea1,3
1
Department of Internal Medicine and Radboud Institute for Molecular Life Sciences,
Radboud University Medical Center, 6525 GA Nijmegen, Netherlands;
email: [email protected], [email protected],
[email protected]
2
Department of Medical Genetics, Iuliu Haţieganu University of Medicine and Pharmacy,
400012 Cluj-Napoca, Romania; email: [email protected]
3
Department of Genomics and Immunoregulation, Life and Medical Sciences Institute,
University of Bonn, 53115 Bonn, Germany; email: [email protected]
Annu. Rev. Immunol. 2021. 39:667–93 Keywords

First published as a Review in Advance on
trained immunity, innate immune memory, epigenetics,
February 26, 2021
immunometabolism, innate immune system
The Annual Review of Immunology is online at
immunol.annualreviews.org Abstract
https://doi.org/10.1146/annurev-immunol-102119-
Traditionally, the innate and adaptive immune systems are differentiated
073855
by their specificity and memory capacity. In recent years, however, this
Copyright © 2021 by Annual Reviews.
paradigm has shifted: Cells of the innate immune system appear to be able
All rights reserved
to gain memory characteristics after transient stimulation, resulting in an
enhanced response upon secondary challenge. This phenomenon has been
called trained immunity. Trained immunity is characterized by nonspecific
increased responsiveness, mediated via extensive metabolic and epigenetic
reprogramming. Trained immunity explains the heterologous effects of vac-
cines, which result in increased protection against secondary infections.
However, in chronic inflammatory conditions, trained immunity can induce
maladaptive effects and contribute to hyperinflammation and progression
of cardiovascular disease, autoinflammatory syndromes, and neuroinflam-
mation. In this review we summarize the current state of the field of trained
immunity, its mechanisms, and its roles in both health and disease.
667
HISTORICAL PERSPECTIVE
As early as in 1931, in the Swedish province of Norrbotten, Carl Naeslund discovered that after
the introduction of bacillus Calmette-Guérin (BCG) vaccination in neonates—who are known to
have immature adaptive immune responses—mortality in the region dropped significantly. This
drop was more than could be explained by a decrease in tuberculosis alone, and he was “tempted
to find an explanation for this much lower mortality among vaccinated children in the idea that
BCG provokes a nonspecific immunity. . .” (1, p. 629). It took almost a century to understand
that the innate immune system can indeed provide protection against reinfection by building a
heterologous immunological memory in innate immune cells, a process that ten years ago was
termed trained immunity (2).
In plants and invertebrate animals, which both lack an adaptive immune system, the innate
immune system is long known to present memory characteristics. Plants that survive an infection
obtain long-term protection against reinfection, a phenomenon called systemic acquired resis-
tance (SAR) (3). SAR spreads from the site of infection throughout the entire plant through sig-
naling molecules, subsequently inducing an enhanced expression of pattern-recognition receptors
(PRRs) and the secretion of antimicrobial proteins (4). This is mediated via epigenetic changes and
can even be even transmitted to the progeny through seeds (5). In invertebrates such as Drosophila
melanogaster, a sublethal dose of Streptococcus pneumoniae primes macrophages and protects the an-
imal for life against a secondary, otherwise lethal reinfection with the same pathogen, despite the
fact that the organism does not have an adaptive immune system (6). A similar phenomenon was
observed in beetles and was shown to go beyond even the first generation (7, 8). Even though the
definition and mechanisms of innate immune memory in vertebrates were only unraveled in the
last decade, older studies showed evidence of BCG protecting athymic nude mice against a sec-
ondary lethal infection with Candida albicans (9), through a process driven by macrophages (10).
In humans, multiple epidemiological studies have shown that live attenuated vaccines can protect
against heterologous microorganisms different from the target pathogen (11, 12). In conclusion,
plants, invertebrates, and vertebrates are all capable of developing adaptive characteristics in in-
nate immune cells, a de facto memory, which results in a nonspecific increased effector function of
the innate immune cell itself. The mechanisms and characteristics of this innate immune memory,
or trained immunity, substantially differ from those of the specific memory induced in cells of the
adaptive immune system by gene recombination.
TRAINED IMMUNITY VERSUS TOLERANCE

The innate immune system is thus capable of remembering first encounters, resulting in a func-
tional change upon secondary stimulation. This can either enhance or repress immune cell func-
tion. The first stimulation will lead to reprogramming of innate immune cells, which can result
in an increased effector function upon secondary stimulation, a process now known as trained
immunity (2), or a repressed effector function upon secondary stimulation, a process called tol-
erance. Tolerance and trained immunity are both innate immune memory phenotypes and are
mediated largely through similar molecular mechanisms (metabolic and epigenetic reprogram-
ming), although with opposite functional results depending on the initial stimulus and the specific
pathways that are induced (Figure 1). The immunological phenotype of trained immunity in hu-
mans lasts from months (13) to at least one year (14), but earlier studies described nonspecific
effects of vaccination in neonates that can have a duration of up to five years (15). Finally, there
are recent studies that even indicate transgenerational effects of trained immunity, similar to what
has been described for innate immune memory in invertebrates. In newborns vaccinated with
BCG, nonspecific beneficial effects and survival were increased when their mothers had prior BCG
668 Bekkering et al.

Secondary
stimulation
with B
Innate immune response
Initial
stimulation
with A
Trained
immunity
Homeostasis
Tolerance
Acetyl CoA
Epigenetic and metabolic
reprogramming
Oxaloacetate Citric acid
NADH
NAD+
Malate Isocitric acid
H2O CO2
Krebs cycle NAD+
Fumarate
FADH2 NADH
FAD α-Ketoglutaric acid
Succinate CO2
NAD+
GTP Succinyl CoA NADH
GDP
Figure 1
Trained immunity versus tolerance. Microbial or endogenous stimuli (stimulus A) can activate innate
immune cells and induce a primary response. Innate immune cells will produce cytokines or activate other
effector functions. Depending on the dose and stimulus, subsequent anti-inflammatory mechanisms can be
induced, and a secondary stimulation (stimulus B) will not lead to another proinflammatory response, so as
to limit tissue damage (tolerance). However, when trained immunity is induced, this leads to enhanced innate
immune effector function upon secondary stimulation (compared to the initial response). Both training and
tolerance are mediated via metabolic and epigenetic changes, although each phenotype has its own signature:
Different genes and pathways will be activated or repressed by different epigenetic and metabolic changes.
Figure adapted from image created with BioRender.com.
www.annualreviews.org • Trained Immunity 669

vaccination (and scarring) as well, indicating a synergistic transgenerational effect of the BCG vac-
cine (16).
Inducers of Trained Immunity

Induction of trained immunity has been studied for microbial but more recently also for nonmi-
crobial stimuli. These studies have focused on myeloid cells such as monocytes and macrophages,
but trained immunity can also be induced in innate lymphoid populations such as natural killer
(NK) cells and innate lymphoid cells (ILCs). Examples of microbial stimuli known to induce
trained immunity in monocytes are live-attenuated vaccines such as the BCG vaccine (13), the
newer live attenuated tuberculosis vaccine MTBVAC (17), the oral polio vaccine (18), the small-
pox vaccine (19), and the measles vaccine (20). The fungal pathogen Candida albicans and its cell
wall component β-glucan (21) were among the first described inducers of trained immunity in
vitro as well as in vivo and are the most used in experimental studies on trained immunity. More
recently the malaria pathogen Plasmodium falciparum (22) and hepatitis B virus (11) were added to
the growing list of microbial inducers of trained immunity. Immune tolerance, on the other hand,
can be induced by lipopolysaccharide (LPS) endotoxins from Escherichia coli (23) and other micro-
bial ligands (24), although at lower concentration LPS is also able to induce trained immunity as
well (24). This dichotomy of dose-dependent training or tolerance is described for more danger-
associated molecular patterns and pathogen-associated molecular patterns (24). Nonmicrobial en-
dogenous inducers of trained immunity include lipoproteins such as oxidized low-density lipopro-
tein (oxLDL) (25), lipoprotein(a) [Lp(a)] (26), and activators of the liver X receptor pathways (27,
28); uric acid (29, 30); catecholamines (31); aldosterone (32); S100-alarmin (33); and interferons
(34). Importantly, all inducers of trained immunity affect the inflammatory functions of myeloid
cells, although with different potential. In general, microbial inducers of trained immunity such
as β-glucan and BCG have a greater potential to induce the inflammatory effector function upon
secondary stimulation than endogenous stimuli such as lipids. Importantly, besides its capacity to
induce trained immunity, BCG is also a strong inducer of T helper type 1 (Th1) responses and
has been employed as a therapeutic alternative in pathologies characterized by exacerbated Th2
responses, such as allergies and asthma (35, 36). Furthermore, due to its strong immunogenicity,
BCG has also been used as an adjuvant to enhance the protective capacity of different types of
vaccines, such as veterinary vaccines (37) and cancer vaccines (38).
MECHANISMS OF TRAINED IMMUNITY

Whereas in adaptive immune memory gene recombination leads to a long-lived specific memory
phenotype resulting in the generation of memory cells, trained immunity develops through dif-
ferent intracellular mechanisms: Upon first encounter of a stimulus, myeloid cells adapt through
epigenetic and metabolic reprogramming (Figure 2), resulting in hyperresponsiveness upon sec-
ondary stimulation. The metabolic and epigenetic changes that underlie trained immunity are
intertwined, and our knowledge of which pathways are involved and interact is still increasing
(39). Importantly, although some metabolic and epigenetic changes appear to be common de-
nominators in trained immunity, such as the Akt/PI3K/mTOR pathway and changes in histone
methylation and acetylation in promoters and enhancers of proinflammatory genes, different stim-
uli can activate different trained immunity programs.
Metabolic Changes Underlying Trained Immunity

Several metabolic pathways are involved in training innate immune cells (Figure 2), such as gly-
colysis, oxidative phosphorylation (OXPHOS), the TCA cycle, and lipid metabolism. Most of the

oxLDL
Smallpox Lp(a)
Measles oxPL β-Glucan
OPV
BCG TLR4/
Uric acid TLR2/
CD36
Dectin-1 Mevalonate
Glucose
Catecholamines
GLUT1 NOD2
Lactate Akt IGF1R

ATP
Glycolysis HIF1α mTOR

Pyruvate β-Adrenergic
receptor
Fatty acid
synthesis
Acetyl-CoA Cholesterol cAMP
Mevalonate synthesis
Oxaloacetate
OXPHOS Citrate Acetyl-CoA PKA
ATP TCA
Fumarate cycle
α-KG Glutamine
Succinate HATs
Me1 Me3 Ac
KDM5 TF TF Proinflammatory
Enhancer Promoter genes
Figure 2
Molecular mechanisms of trained immunity. Inducers of trained immunity, such as β-glucan, BCG, uric acid, and several (oxidized)
lipids, activate intracellular metabolic pathways, each via different receptors. The most common pathway is the Akt-HIF1α-mTOR
pathway, which ultimately leads to the upregulation of glycolysis, the TCA cycle, and also the cholesterol synthesis pathway.
Metabolites from these pathways can in turn regulate epigenetic remodeling of histones; for example, acetyl-CoA serves as an acetyl
donor for histone acetyltransferases. Fumarate, on the other hand, a TCA cycle metabolite, inhibits lysine-demethylase KDM5, thereby
increasing histone methylation, another epigenetic mark associated with trained immunity. Catecholamines, via activation of the
beta-adrenergic receptor, are inducing epigenetic and metabolic changes via the cAMP-PKA pathway. Abbreviations: Ac, acetylation;
ATP, adenosine triphosphate; α-KG, α-ketoglutarate; BCG, bacillus Calmette-Guérin; cAMP, cyclic adenosine monophosphate;
GLUT1, glucose transporter 1; HAT, histone acetyl transferase; HIF1α, hypoxia-inducible factor 1 alpha; IGF1R, insulin-like growth
factor 1 receptor; KDM5, lysin-specific demethylase 5; Lp(a), lipoprotein(a); Me1, monomethylation; Me3, trimethylation; mTOR,
mammalian target of rapamycin; NOD2, nucleotide-binding oligomerization domain–containing protein 2; OPV, oral polio vaccine;
oxLDL, oxidized low-density lipoprotein; OXPHOS, oxidative phosphorylation; oxPL, oxidized phospholipid; PKA, protein kinase A;
TCA, tricarboxylic acid; TF, transcription factor; TLR, Toll-like receptor. Figure adapted from image created with BioRender.com.
evidence listed here comes from studies using an in vitro protocol for inducing trained immu-
nity (40), although the majority of findings are confirmed in in vivo animal models or human
studies.
Glycolysis plays a central role in cellular metabolism, and its upregulation is essential during
the activation of macrophages (41). Upregulation of glycolysis results in an increased uptake of
glucose, which is subsequently converted into pyruvate and transformed into lactate, which is then

released from the cell. Although glycolysis is much less efficient than OXPHOS for the generation
of ATP, glycolytic enzymes can be rapidly induced. Cheng et al. (42) showed that in β-glucan-
trained monocytes, glucose consumption is increased, indicating upregulation of the glycolysis
pathway. Arts et al. (43) confirmed that glucose was converted into lactate via an increased activity
of the glycolysis pathway. Several metabolites from this pathway can act as cofactors for DNA
and histone methyltransferases (44), indicating a connection between metabolic pathways and
epigenetic reprogramming. In β-glucan-trained monocytes, genes involved in glycolysis such as
hexokinase and pyruvate kinase are epigenetically modified with activating histone marks (23).
Just as in β-glucan-induced training, BCG- and oxLDL-trained monocytes are also characterized
by an upregulation of glycolysis (45, 46).
The TCA cycle uses the energy from acetyl-CoA and transfers it to OXPHOS, which results in
ATP production. In the first studies with β-glucan-trained monocytes, it was shown that β-glucan
induces a shift from OXPHOS to glycolysis, also known as the Warburg effect (42). Instead of
providing energy by ATP production, there is an anabolic repurposing of TCA metabolites (43).
Glutamine replenishment of the TCA cycle leads to the accumulation of fumarate, which can in-
duce trained immunity by inhibiting the activity of histone demethylase KDM5. This is followed
by persistence of histone methylation and opening of the chromatin that is needed for gene tran-
scription and the increased production of proinflammatory cytokines upon restimulation. Sub-
sequent studies showed that the balance between OXPHOS and glycolysis is dependent on the
specific concentration of β-glucan used in the studies: A lower dose of β-glucan that was also as-
sociated with a hyperresponsive trained phenotype induced an upregulation of both OXPHOS
and glycolysis in trained monocytes (47). This activation of OXPHOS is due to enrichment of the
activating histone modification H3K4me1 on the enhancers of specific metabolic enzymes by the
histone methyltransferase Set7 (47). In BCG- and oxLDL-trained monocytes, a similar upregula-
tion of both OXPHOS and glycolysis is also observed (45, 48). Other intermediates from the TCA
cycle such as α-ketoglutarate, a cofactor for JmjC demethylases (49); succinate; and acetyl-CoA
play important roles in the regulation of inflammation as well. Succinate can stabilize HIF1α,
thereby promoting IL-1β transcription (50). Acetyl-CoA serves as an acetyl donor for histone
acetyl transferases (51), which are upregulated in the context of trained immunity. Examples of
acetylated genes in trained immunity are genes for hexokinase and lactate dehydrogenase, which
in turn promote glycolysis (52). Finally, itaconate, another TCA cycle metabolite, is an important
node between trained immunity and tolerance in that it inhibits inflammation and trained immu-
nity. In this sense, itaconate is able to mimic the tolerizing effects of LPS and inhibit the induction
of trained immunity by β-glucan through the inhibition of mitochondrial metabolism, leading to
decreased responsiveness after secondary stimulation (53).
During the induction of trained immunity by β-glucan, in addition to upregulation of glycolysis
and OXPHOS and repurposing of the TCA cycle, an upregulation of cholesterol synthesis path-
way genes was observed (23). Inhibition of the cholesterol synthesis pathway by statins prevented
the induction of training for β-glucan, BCG, and oxidized LDL, indicating that the cholesterol
synthesis pathway is essential for trained immunity (54). Further characterization of the pathway
revealed that accumulation of mevalonate is responsible for the induction and further amplifica-
tion of trained immunity through the IGF1R-Akt-mTOR pathway. Further evidence for a role for
mevalonate in trained immunity comes from the characterization of monocytes from patients with
deleterious mutations in mevalonate kinase who subsequently accumulate high levels of meval-
onate. These patients with the hyperimmunoglobulin D syndrome (HIDS) are characterized by
recurrent attacks of sterile inflammation and fever, and their monocyte phenotype resembles an
endogenous trained immune phenotype, with increased cytokine production, upregulation of gly-
colysis, and epigenetic changes (54).

Fatty acid synthesis contributes to inflammation by inducing intracellular stress and activa-
tion of the NLRP3 inflammasome (55), whereas fatty acid oxidation is generally believed to be
anti-inflammatory. A role for the fatty acid synthesis pathway in trained immunity was demon-
strated by Mitroulis et al. (56), who showed that β-glucan training induces a reduction in fatty acid
metabolites in hematopoietic progenitors. As a result, intracellular lipids in β-glucan-trained cells
appeared shorter and more saturated. Inhibition of the fatty acid synthesis pathway during the first
24-h stimulation period, however, does not prevent training (43). On the other hand, inhibition
of fatty acid synthesis during restimulation blunts the trained immunity phenotype (32). Trained
immunity induced by aldosterone induces fatty acid synthesis via activation of the mineralocorti-
coid receptor, ultimately leading to increased trimethylation of lysine 4 on histone 3 (H3K4me3)
on genes involved in the fatty acid synthesis pathway as well as an increased production of IL-6
and TNF-α. Preincubation of aldosterone-trained cells with a fatty acid synthesis inhibitor before
restimulation prevented augmented cytokine production, showing a role for fatty acid synthesis in
the secondary effector function. Monocyte-derived macrophages from patients with hyperaldos-
teronism, who also have increased arterial wall inflammation, showed a similar increase in TNF-α
production upon stimulation compared to trained cells in vitro (57). In contrast, monocytes from
patients with sepsis, characterized by immune tolerance, showed lower proinflammatory cytokine
production accompanied by impaired beta-oxidation.
Trained immunity is dependent on distinct epigenetic programs. Due to a first encounter

with a stimulus, monocytes are rapidly activated and upregulate gene transcription, which is asso-
ciated with a rapid acquisition of activating histone modifications. After removal of the stimulus,
however, some of these epigenetic marks persist, which leads to faster and stronger activation
of gene transcription upon secondary stimulation (58). Important epigenetic marks involved in
trained immunity are H3K4me3, which marks active promotors; H3K4me1, which marks dis-
tal enhancers; and H3K27 acetylation, which marks both active enhancers and promotor regions
(23, 59) (Figure 1). Repressive histone marks important for trained immunity are H3K9me3 and
H3K27me3, which are reduced during training in some cases (45, 60, 61), although these did not
play a role in the early priming phase of innate immune memory induced by β-glucan in vitro (59),
indicating stimulus-specific epigenetic changes.
In addition to histone modifications, long noncoding RNAs (lncRNAs) were described to link
epigenetic and metabolic changes in trained immunity (62, 63) through immune gene–priming
lncRNAs that function as transporters for methyl transferases within a topologically associated
domain of the chromatin that contains trainable genes. However, this mechanism is only studied
in β-glucan-trained cells and warrants further investigation in other models of trained immunity.
Finally, the contribution of DNA (de)methylation to the development of trained immunity needs
to be investigated in more detail. Preliminary studies show that the induction of LPS tolerance
in vitro leads to stable and long-term specific DNA methylation changes, but less is known about
these signatures in trained immunity (59). In a recent study with BCG-vaccinated human adults
in vivo, DNA methylation appeared useful to discriminate responders (human volunteers that
undergo trained immunity upon BCG vaccination) from nonresponders. Enhanced containment
of Mycobacterium tuberculosis replication after BCG vaccination in responders was accompanied by
a wide loss of DNA methylation on promoters of inflammatory genes compared to nonresponders
(64, 65). Further studies of the role of DNA methylation in trained immunity are warranted.
REPROGRAMMING OF HEMATOPOIETIC PROGENITOR CELLS

Trained immunity was first described for mature myeloid cells such as monocytes and NK cells (13,
21, 66). The average half-life of myeloid cells in the circulation is only a few days, yet circulating

cells with a trained immunity phenotype have been described to exist months or even a year follow-
ing in vivo induction of trained immunity with BCG. This strongly suggests that progenitor cells
might also be reprogrammed in the context of trained immunity. Indeed, recent work showed that
trained immunity can occur in bone marrow progenitor cells in addition to training occurring in
mature myeloid cells. Mitroulis et al. (56) showed that modulation of bone marrow progenitors is
an integral component of β-glucan training in mice in vivo. β-Glucan training induced reprogram-
ming of hematopoietic stem cell progenitors via IL-1β, and this was also associated with an upreg-
ulation of glycolysis and the cholesterol synthesis pathway in progenitor cells, similar to the case
of trained monocytes. This resulted in the expansion of myeloid-biased hematopoietic stem and
progenitor cells (HSPCs), which was essential for increased protection against reinfection. BCG
was also shown to train and expand hematopoietic stem cells in a mouse model in vivo, a process
that was dependent on IFN-γ signaling (67). Bone marrow–derived macrophages of BCG-trained
mice subsequently acquired protection against infection with M. tuberculosis, which was accompa-
nied by epigenetic changes such as H3K4me3 and H3K27ac. Transplantation of the bone marrow
of BCG-trained mice into naive mice then conferred protection against reinfection, confirming
long-term reprogramming of the bone marrow. These observations were confirmed in a study
with human volunteers in which vaccination with BCG led to transcriptional and epigenetic repro-
gramming of the bone marrow hematopoietic stem cell progenitors up to 90 days after initial vacci-
nation, resulting in a myeloid bias and increased protection against reinfection (68, 69). Combined
transcriptional and genetic analysis demonstrated an important role of transcription factors such
as hepatic nuclear factors 1a and 1b in this process (69). In Ldlr−/− mice, a four-week Western diet
followed by a four-week chow diet induced similar reprogramming of the bone marrow via tran-
scriptomic and epigenetic changes (70). This was mediated via the NLRP3 inflammasome and IL-
1β and resulted in increased proliferation and enhanced innate immune responses in the mice. The
role of bone marrow reprogramming in other settings of trained immunity is under investigation.
CENTRAL VERSUS PERIPHERAL INDUCTION

OF TRAINED IMMUNITY
Monocytes and their bone marrow progenitors are not the only myeloid cells to undergo trained
immunity. Similar properties have been described for various populations of tissue macrophages
and dendritic cells (DCs). Indeed, one can distinguish activation of trained immunity at the level
of bone marrow progenitors and monocytes (central activation) from activation of myeloid cells
such as macrophages and DCs in the peripheral tissues (peripheral activation) (Figure 3). In
the lung, macrophages are capable of obtaining a memory phenotype upon a viral challenge.
Lungs of mice that had previously been exposed to gammaherpesvirus showed decreased dust
mite–induced asthma complications. This phenotype was dependent on long-term memory in
monocyte-derived alveolar macrophages conferring protection against allergic responses (71).
Adenovirus infection induced remodeling of resident macrophages, resulting in more pronounced
antibacterial immunity upon reinfection (72). This was dependent on CD8+ T lymphocytes,
thereby showing close collaboration between trained immunity and adaptive immunity. Finally,
Hoyer et al. (73) showed that local injury such as sepsis, myocardial infarction (MI), and stroke
could lead to macrophage memory in remote organs, leaving them susceptible for increased acti-
vation. In the lung specifically, this was dependent on local IFN-γ priming. Alveolar macrophages
are also sensitive to inflammation-induced epigenetic changes leading to long-term immunoparal-
ysis and tolerance (74).
Microglia, resident macrophages of the central nervous system, play a vital role in normal brain
functions but are also sensitive to innate immune memory under certain conditions (75). In mouse

Bone marrow Circulation
Central trained immunity

HSC MPP CMP GMP Monocyte
High-cholesterol
Western diet
Vaccine/adjuvant
BCG or β-glucan
Nonimmune Immune
Peripheral trained immunity
Endothelial cells
NK cells
ILCs
Macrophage
Epithelial cells
Enhanced
VSMC DC effector function
Fibroblast
Figure 3
Central versus peripheral trained immunity. Although trained immunity was first discovered in circulating
cells such as monocytes and NK cells, these cells have a short life span; it is shorter than the duration of
trained immunity in humans in vivo. We now know that progenitor cells of the bone marrow can also obtain
a memory phenotype, for example through vaccination or a Western diet, that is then transmitted to their
progeny, the cells in circulation. Eventually, these circulating cells migrate to tissues, where they have
enhanced effector functions as tissue macrophages and NK cells. Additionally, other immune cells in the
tissues, such as DCs and ILCs, are capable of obtaining a trained immunity phenotype as well. Finally,
nonimmune cells such as endothelial cells, epithelial cells, fibroblasts, and VSMCs are described to have
memory capacities as well (78, 79, 94–96). Abbreviations: BCG, bacillus Calmette-Guérin; CMP, common
myeloid progenitor; DC, dendritic cell; GMP, granulocyte-macrophage progenitor; HSC, hematopoietic
stem cell; ILC, innate lymphoid cell; MPP, myeloid progenitor population; NK, natural killer; VSMC,
vascular smooth muscle cell. Figure adapted from image created with BioRender.com.
models of Alzheimer disease and stroke, both innate immune training and tolerance were shown in
brain-resident microglia via epigenetic reprogramming. This memory lasted for at least six months
(76) but is also thought to be transgenerational (77). The important role played by chronic inflam-
mation in neurodegenerative processes makes trained immunity a potential important therapeutic
target in Alzheimer and Parkinson diseases.
The field of DC memory is relatively new, although there are indications that DCs can obtain
a memory phenotype as well. In the lung, local modulation of DCs after the resolution of pneu-
monia resulted in long-term susceptibility to secondary infections, indicating DC tolerance (78).
This was further studied by Hole et al., who showed that DCs can be trained to exhibit enhanced
transcriptional activation upon secondary stimulation, a process driven by epigenetic modifica-
tions (79). The induction of DC memory might be useful in optimizing vaccination strategies
for better clearance of infections. Indeed, one can argue that the adjuvanticity effect on antigen-
presenting cells is a functional program similar to induction of trained immunity.

TRAINED IMMUNITY IN LYMPHOID IMMUNE CELLS
In addition to myeloid cells, trained immunity has been described for several populations of cells
of the lymphoid lineage, such as NK cells and ILCs (80, 81). NK cells can obtain a memory pheno-
type and enhanced effector function when exposed to BCG in humans in vivo. In healthy human
volunteers, BCG vaccination leads to enhanced production of cytokines by NK cells three months
later (66). Similarly, the influenza vaccine is capable of inducing NK cell memory, resulting in en-
hanced NK cell activation upon secondary stimulation (82). However, previous cytomegalovirus
(CMV) infection can impair the induction of NK cell memory to influenza (83). In a human ex-
perimental malaria model, NK cell memory lasted at least for four months, but here the induction
of NK cell memory required the help of T cells (84). Other microbial stimuli described to in-
duce NK cell memory are haptens (85) and CMV (86). But not only microbial stimuli can induce
NK cell training. A combination of IL-12, IL-15, and IL-18 was shown to induce memory-like
NK cells, resulting in effector cells with superior control of leukemic cells (87) and enhanced
IFN-γ production (88). This affects tumor immune surveillance of NK cells and might be very
significant for clinical immunotherapy. In the uterus, training of NK cells and subsequent epige-
netic modifications are essential for their function in successful placentation (89). Mechanistically,
both metabolic and epigenetic reprogramming are shown to underlie NK cell memory, similar to
trained immunity in monocytes (90–93).
ILC memory research is still in its infancy, but recent studies show that liver-resident group
1 ILCs (ILC1s) can be primed in a non-antigen-specific fashion, inducing stable transcriptional,
epigenetic, and phenotypic changes up to one month after CMV infection (94). This is driven by
cytokines. ILC2s can also obtain immune memory characteristics upon stimulation with allergens
(95), similar to hapten-induced NK cell memory, as described above. Further research into the
roles of ILC memory in health and disease is warranted.
TRAINED IMMUNITY IN NONIMMUNE CELLS

In addition to immune cells, nonimmune cells can also play a role in the response to pathogens
and can produce cytokines and antimicrobial factors. Recently, it has been suggested that they
could also be capable of developing memory characteristics, in a concept called expanded
trained immunity (96). Indeed, in mesenchymal stem cells, trained immunity can be induced via
microRNA expression and DNA methylation changes upon LPS exposure. Proinflammatory
cytokine expression was maintained even in the absence of the stimulus (97). In the skin, epithelial
stem cells are capable of immune memory after chemical, mechanical, and microbial stimulation,
resulting in enhanced healing capacity. This was mediated via epigenetic changes similar to
monocyte training and has been termed inflammatory memory (98). Furthermore, epithelial
progenitor cells in the respiratory tract can acquire memory during allergic inflammatory disease,
which is mediated via long-term epigenetic changes (99). A similar observation was made for
mature bronchial epithelial cells that can remember infection through epigenetic regulation.
Pseudomonas aeruginosa flagellin induces trained immunity in epithelial cells and increased proin-
flammatory cytokine production upon unrelated secondary stimulation, mediated via histone
acetylation and H3K9 methylation (100).
Endothelial cells can produce cytokines and chemokines, and they play a major role in the
development of atherosclerotic plaques. El-Osta et al. (101) showed that exposure of cultured
endothelial cells in vitro to transient high glucose concentrations caused persistent hyperin-
flammation through epigenetic changes and altered gene expression during a subsequent pe-
riod of normoglycemia, a phenomenon known as hyperglycemic memory. Furthermore, oxidized

phospholipids present on Lp(a) were recently shown to induce metabolic reprogramming of
endothelial cells, resulting in a proinflammatory and atherogenic phenotype (102), similar to
monocyte training by Lp(a) (26). Whether these changes are long-lasting is a topic for future
studies. Human coronary smooth muscle cells are also amenable to the induction of trained im-
munity. oxLDL or BCG priming of smooth muscle cells in vitro led to increased proinflammatory
cytokine production upon restimulation seven days later, which was mediated via mTOR-HIF1α
signaling and changes in glycolysis and the cholesterol synthesis pathway as well as epigenetic
changes (103).
Finally, synovial fibroblasts can become persistently activated via long-term epigenetic changes
resulting in enhanced inflammation upon stimulation in rheumatoid arthritis (104). In periodontal
disease, human gingival fibroblasts can also sustain an inflammatory phenotype (105), a process
that involves epigenetic changes (106, 107). Interestingly, not all fibroblasts can obtain a memory
phenotype, as dermal fibroblasts, for example, were not able to undergo trained immunity (108).
Further research is warranted to assess the role of trained immunity in (non)immune cells in vivo.
TRAINED IMMUNITY IN HEALTH AND DISEASE

From an evolutionary perspective, trained immunity most likely evolved to protect the host against
reinfection, in species that lack adaptive immunity or in newborns that do not yet have functional
adaptive immunity. A maladaptive effect of trained immunity, however, can potentially contribute
to several disease states in which hyperinflammation or immunosuppression is detrimental for
disease pathology. The induction of trained immunity or lack thereof can thereby contribute to
both health and disease (Figure 4).
Protection Against Reinfection

Neonates are fully dependent on their innate immune system, in addition to antibody supple-
mentation in breast milk. It was therefore initially surprising that vaccination with BCG led to
protection against unrelated secondary infections, both viral and bacterial (12, 109, 110). It is now
known that several live attenuated vaccines have this beneficial, nonspecific protective effect lead-
ing to decreased childhood mortality. Inactivated vaccines such as the diphtheria-tetanus-pertussis
(DTP) vaccine have been suggested to induce an opposing program and can diminish the induc-
tion of trained immunity and possibly even lead to increased childhood mortality, especially among
vaccinated girls (20, 111). This is important for future vaccination strategies and also for the order
in which vaccination programs are designed. These epidemiological studies in neonates have been
complemented by investigations showing nonspecific protective effects of BCG in adults. In ado-
lescents already vaccinated with BCG at birth, revaccination with either BCG or the new H4IC31
vaccine leads to a 70% reduction of respiratory tract infections compared to the placebo controls
(112). In adult human volunteers, BCG vaccination leads to decreased experimental viral infec-
tion via the yellow fever vaccine one month after vaccination, a process mediated by IL-1β (113).
Another explorative randomized trial studied the effects of BCG on Vi polysaccharide typhoid
fever vaccine, an inactive vaccine that induces tolerance (114). Prior BCG vaccination prevented
the tolerizing effects of typhoid vaccine, similar to the effects observed for BCG prior to DTP
vaccination (115). In individuals aged more than 65 years, BCG can protect against respiratory
tract infections, indicating potential for boosting immune function in the elderly (116, 117). Fi-
nally, BCG vaccination was shown to alter the clinical and immunological response to malaria in
a human trial, indicating a potential for malaria vaccine strategies (118).
A number of animal and human studies have now demonstrated that trained immunity in-
duced by several different stimuli can give rise to increased protection against reinfection in the
ity
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COVID-19 Organ
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Mucosal Allergies
tolerance
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Benefic
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Cardiovascular
Trained immunity disease
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Figure 4
Trained immunity in health and disease. Trained immunity is associated with both health and disease states,
and therefore there is therapeutic potential in either inducing it or inhibiting it. Trained immunity can
induce increased protection against reinfection, which can be used to optimize vaccination strategies or for
protection against, for example, COVID-19. It is important in the induction of mucosal tolerance, and it is
already being used to treat bladder cancer. On the other hand, several chronic inflammatory diseases are
characterized by an inappropriate trained immunity phenotype, such as cardiovascular diseases, allergies,
transplantation rejection, and autoinflammatory diseases. Here, it will be more beneficial to inhibit trained
immunity. Abbreviation: COVID-19, coronavirus disease 2019. Figure adapted from image created with
BioRender.com.
host. In a recent mouse model, β-glucan training led to protection against Leishmania infection
via upregulated expression of IL-1 and IL-32 (68). A similar IL-1β-dependent protection against
M. tuberculosis infection was shown upon β-glucan training in mice, a process that was also me-
diated via reprogramming of the bone marrow. Mice latently infected with gammaherpesvirus or
CMV show antigen-aspecific resistance to infection with Listeria monocytogenes and Yersinia pestis,
a process that was mediated by increased innate immune activation (119). Intraperitoneal stim-
ulation with CpG dinucleotides protected neutropenic mice against intracerebral Escherichia coli

infection, indicating that the protection against reinfection can also be induced in remote organs
and this protection can cross the blood-brain barrier (120). Locally in the lungs, respiratory in-
fection with attenuated Bordetella pertussis protected against the highly pathogenic influenza A
virus by dampening cytokine production, indicating protection by the induction of immune toler-
ance (121). S100-alarmin-induced training, on the other hand, protected newborns from neonatal
sepsis and immune tolerance (33). This is important, as sepsis (and the accompanying immune
tolerance) generally leads to increased susceptibility to secondary infections (122). Not only can
trained immunity prevent sepsis, but immunoparalysis in sepsis patients can even be reversed by
the induction of trained immunity (123), a process that was also unraveled mechanistically in vitro
and involves reversal of epigenetic changes induced by immune tolerance (59). In conclusion, opti-
mal induction of trained immunity can lead to enhanced protection against infections and reverse
immune-tolerized states.
Trained Immunity Against SARS-CoV-2 Infection?

Based on the evidence that BCG induces rapid viral clearance in several human studies (113) and
can lead to protection against reinfection, trained immunity was hypothesized to be a tool for
reducing susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (124).
SARS-CoV-2 infection is mild in most cases but can rapidly progress to severe pneumonia and
hyperinflammatory phenotypes in a proportion of patients. Elderly individuals and those with
comorbidities often leading to a compromised response to viral infections are at increased risk of
developing severe disease. It is now proposed that boosting of the innate immune response in these
individuals by inducing trained immunity might protect against severe SARS-CoV-2 infection at
least for a limited amount of time and until a specific vaccine is developed (124). Although the
first epidemiological studies seemed to indicate lower infection rates in countries with active BCG
vaccination policies (125), causality cannot be established and several biases cannot be excluded,
such as demographics, genetics, and infectious burden (126). Also, reporting and diagnosing of
coronavirus disease 2019 (COVID-19) cases differ greatly among countries, making these epi-
demiological studies hard to interpret. Furthermore, it is not known whether a trained monocyte
phenotype persists for more than one year after vaccination (14). Therefore, several randomized
controlled trials have now started to (re)induce heterologous protection against SARS-CoV-2 us-
ing BCG (127, 128), and the oral polio vaccine and measles vaccine are under consideration for
additional randomized controlled trials (129).
Trained Immunity in Cancer

In cancer, the activation of the immune system is a double-edged sword. Efficient activation of the
immune system can induce antitumor effects and elimination of cancer, but excessive or chronic
inflammation can also promote tumor progression. BCG vaccination is shown to have antitu-
mor effects and is already in use for the treatment of bladder cancer, melanoma, leukemia, and
lymphoma (130–132). The antitumor capacity of BCG is regulated via the induction of trained
immunity, a process in which autophagy plays an important role (133). Furthermore, the induction
of trained immunity by β-glucan was shown to protect against chemotherapy-induced myelosup-
pression and inhibit the growth of Lewis lung carcinoma (56, 134). Indeed, β-glucan has long
been used as an immunostimulatory agent in cancer in countries in East Asia, and in the United
States it is currently in clinical trials in combination with checkpoint inhibitors (https://www.
clinicaltrials.gov). Further studies are warranted to fully understand the role of trained immu-
nity in cancer and to harness its therapeutic potential (135).

Trained Immunity in Intestinal Homeostasis
In the gut, innate immune memory likely can have both a beneficial role and a deleterious ef-
fect in inflammatory bowel disease. Cells of the gastrointestinal tract are continuously exposed to
relatively high concentrations of LPS through the microbiome and diet. In this sense, intestinal
stromal cells are able to provide long-lasting immune responses against diverse pathogens and trig-
ger the quick recruitment of immune cells to the site of infection (136). Cellular tolerance and an
increased threshold of cellular activation are continuously induced in the healthy gut mucosa and
are likely beneficial for preventing hyperinflammation (137). The gut microbiota is hypothesized
to regulate the induction of innate immune memory (138), but external stimuli such as β-glucans
can also affect intestinal inflammation and epithelial barrier function (139) in both beneficial and
deleterious ways. Using a model of dextran sodium sulfate (DSS)-induced colitis, Heinsbroek et al.
(140) showed that orally delivered β-glucans can aggravate intestinal inflammation. On the other
hand, mice lacking dectin-1, the receptor for β-glucans, also exhibit increased susceptibility to
DSS-induced colitis; this also occurs in humans with specific polymorphisms in dectin-1 (141).
Furthermore, prolonged oral treatment of mice with antifungal drugs increases disease severity
in models of chronic colitis as well as chronic allergic airways disease, indicating the importance
of a healthy fungal community in the gut but also highlighting the influence of gut microbiota on
peripheral immune responses and allergic diseases (142). Further research is warranted to better
understand the roles of trained immunity in the gut in both health and disease.
Cardiometabolic Disease
Monocytes and macrophages play a pivotal role in the disease progression of cardiometabolic dis-
orders, such as atherosclerosis, diabetes, and obesity. Several lines of evidence now indicate that
in these chronic inflammatory cardiometabolic diseases, trained immunity can play a detrimental
role (143–145). First of all, trained immunity may explain the known epidemiological association
between the infectious burden and increased cardiovascular disease risk, as discussed in Refer-
ence 146. Secondly, in addition to microbial stimuli, several endogenous atherogenic stimuli are
able to induce trained innate immunity in monocytes in vitro, such as oxLDL (25), Lp(a) (26),
catecholamines (31), and aldosterone (32).
Furthermore, hyperglycemia can induce innate immune memory via long-term epigenetic
changes in both monocytes and endothelial cells (101, 147, 148). In vitro, training of mono-
cytes with oxLDL in high-glucose conditions boosted cytokine production capacity compared
to oxLDL training in normoglycemic conditions (46). Recently, it was shown that diabetes also
induces enhanced proliferation of HSPCs in the bone marrow and a myeloid bias, leading to
augmented circulating myeloid cell numbers and enhanced atherosclerosis (149, 150). This was
regulated via the interaction between endothelial cells and bone marrow progenitor cells. Fur-
thermore, in an atherosclerosis-prone Ldlr−/− mouse model, a four-week Western diet induced
long-term reprogramming of cells of the myeloid lineage, a process that originated in changes in
bone marrow progenitor cells (70). These inflammatory changes persisted for at least four weeks
after reversal of the diet to normal chow.
In human observational studies, monocytes from patients with symptomatic atherosclerosis
exhibited a trained immunity phenotype with increased proinflammatory cytokine production,
accompanied by metabolic and epigenetic changes compared to healthy controls (61). This was
confirmed in another study by Shirai et al. (151), who showed that monocytes from patients
with coronary atherosclerosis have a proinflammatory phenotype and enhanced glycolytic activ-
ity, even after differentiation into macrophages in vitro. In treatment-naive patients with familial
hypercholesterolemia, monocytes showed a trained immunity phenotype, in contrast to healthy

controls, characterized by an increased proinflammatory phenotype, that persisted up to three
months after lipid-lowering therapy with statins, indicating a memory capacity and an involve-
ment of the bone marrow (60). A similar hyperinflammatory monocyte phenotype was observed
in patients with elevated levels of Lp(a) (26), who also had increased vascular wall inflammation as
measured with FDG-PET/CT (fluorodeoxyglucose positron emission tomography/computed to-
mography). This proinflammatory phenotype was not reversed upon Lp(a) lowering with PCSK9
for 90 days (152). Lp(a) was recently shown to induce hematopoietic reprogramming as well (153).
Catecholamines induce trained immunity in monocytes in vitro. In patients with pheochromo-
cytoma, who have chronic increased levels of catecholamines, increased systemic inflammation and
an elevated cytokine production capacity of myeloid cells were observed. These did not decline
after surgical removal of the tumor, which indicates a memory phenotype in the circulating cells.
And indeed, trained immunity was confirmed by epigenetic analysis showing long-term enriched
H3K4me3 in promoter regions of proinflammatory genes (31).
In a small proof-of-principle study, it was shown that lifestyle intervention might be an inter-
esting therapeutic target for decreasing inflammation in patients at risk for cardiovascular diseases.
In a group of obese and hypertensive patients, sedentary behavior was reduced over a 16-week pe-
riod, which induced a reduction in cytokine production capacity upon secondary stimulation. This
was accompanied by anti-inflammatory changes in intracellular metabolism, such as a decrease in
glycolysis and OXPHOS. It would be interesting to study whether these observed changes were
also accompanied by long-term epigenetic changes. Lifestyle changes are increasingly seen as a
potential therapy for cardiovascular disease and the underlying innate immune memory, and it
will be interesting to study the effects on trained immunity (154).
Neurodegenerative Disease
Microglia are the resident macrophages of the central nervous system and play a vital role in nor-
mal brain function and pathologies. Microglial immune memory has now been suggested as an
underlying cause of neuroinflammation (75). As mentioned above, microglia can be trained, so as
to result in metabolic and epigenetic changes. This was first shown by Wendeln et al. (76), who
showed that both immune training and tolerance can be induced in brain-resident macrophages
via changes in H3K4me1 and H3K27ac, which lasted for at least six months. The imprinted mem-
ory, in the case of trained immunity induction, resulted in exacerbated cerebral inflammation and
beta-amyloidosis in a mouse model of Alzheimer disease. When tolerance was induced, on the
other hand, disease pathology was alleviated. Similar context-dependent observations in the mi-
croglia were made by Datta et al. (155), who showed that this process was dependent on histone
acetyltransferases HDAC1/2. We now know that microglial immune memory can be induced by
both microbial (156) and endogenous stimuli such as stress (157), and it is thought to be trans-
generational (77) or at least long-term, with an important role for IL-1β in early life (158–160).
In the brain, vascular diseases such as arteriolosclerosis underlie cognitive decline and demen-
tia. Here, trained immunity might also contribute to the pathology of disease. In an elderly cohort
of individuals with cerebral small-vessel disease, monocytes showed a proinflammatory phenotype
and disease progression associated with increased cytokine production capacity (161).
Autoinflammatory and Allergic Diseases

Besides cardiovascular and neuroinflammatory diseases, patients with several other autoinflam-
matory diseases or allergies have been described to suffer from the detrimental effects of hyper-
inflammation in the context of trained immunity (162). Patients with HIDS suffer from recurrent
febrile episodes and hyperinflammation and are characterized by mevalonate kinase deficiency

(163). Monocytes isolated from these patients exhibit a trained phenotype, as shown by increased
production of proinflammatory cytokines as well as metabolic and epigenetic rewiring. It is now
known that the accumulation of mevalonate is responsible for these effects, through a positive
loop activated by IGF1R (54). A similar trained immunity phenotype is likely responsible for the
hyperinflammatory patterns in other autoinflammatory syndromes such as familial Mediterranean
fever, Behcet disease, and Schnitzler syndrome. Future studies are warranted to establish the in-
volvement of trained immunity in these diseases.
In patients with systemic lupus erythematosus, hematopoietic stem and progenitor cells show
transcriptomic reprogramming and myeloid skewing similar to what has been described in trained
immunity, resulting in increased circulating neutrophil numbers, increased inflammation, and dis-
ease progression (164). In gouty arthritis, monocytes become hyperinflammatory due to priming
with soluble uric acid, leading to increased proinflammatory cytokine production upon restimula-
tion, which is mediated via epigenetic and metabolic reprogramming (29, 30). In murine autoim-
mune arthritis, myeloid skewing occurs in HSPCs, resulting in increased inflammation. Whether
this is mediated via metabolic and epigenetic changes, however, requires further investigation
(165). The therapeutic potential of inducing trained immunity or tolerance in autoinflammatory
diseases was elegantly studied by Jeljeli et al. (166). They showed that the induction of LPS tol-
erance alleviated fibrosis in a mouse model of systemic sclerosis, whereas induction of training by
BCG exacerbated disease progression. The induction of two opposing immune programs resulted
in opposing disease states, collectively mediated via innate immune activation (166).
Recently, a potential role for trained immunity and epigenetic changes was hypothesized to
underlie food allergy (167). Allergic children have an increased innate immune response com-
pared to nonallergic children (168) that is already present in early life (169). Monocytes from
children with food allergy show changes in innate immune function resembling a trained pheno-
type (170), although the underlying epigenetic changes and memory upon removal of the stimulus
are still under investigation. The development of food allergy later in life, however, can be pre-
dicted from monocyte immune responses at birth, indicating some sort of programmed phenotype
(171). However, the induction of a balanced state of trained immunity has also been suggested to
prevent (food) allergy. Several studies have shown the beneficial effects of vaccines on the develop-
ment of (food) allergies (172). Prior BCG vaccination was shown to suppress allergic sensitization
in an animal model of allergic airway disease (173). This was confirmed in another study in which
gammaherpesvirus infection provided protection against allergic asthma via activation of the in-
nate immune system (71). In a similar fashion, whole-cell pertussis vaccination decreased the risk
of IgE-mediated food allergy (174). Large randomized clinical trials are being conducted to study
whether BCG vaccination at birth prevents the development of food allergy in countries with low
infectious burden (175). To improve prevention or treatment strategies, more research is needed
to understand the difference between the potential of trained immunity to prevent food allergy
and the detrimental effects of trained immunity once the allergy is established. On the other hand,
these data could also mirror different programs of trained immunity. Indeed, trained immunity
is a means by which innate immune cells gain a different function through long-term epigenetic
changes, rather than a specific transcriptional program. Some of these changes can be protective in
certain circumstances (a protective trained immunity program), while other changes can represent
the molecular substrate of disease (a deleterious trained immunity program).
Organ Transplantation
The role of innate immune cells in organ transplantation is poorly studied, and the focus has
long been on the role of the adaptive immune system. However, recent advances have shown

that the innate immune system not only plays a role in the initial immune response against
allografts but also partially mediates long-term chronic rejection (176). Braza et al. (177) showed
that monocytes in the allograft obtain a trained immunity phenotype that is induced by vimentin
and HMGB1, and this results in allograft rejection. Inhibition of trained immunity by mTOR
high-density lipoprotein (HDL) nanoparticles, on the other hand, leads to successful organ
transplantation, indicating a potential for transplantation therapeutics (177).
CLINICAL IMPLICATIONS AND FUTURE PERSPECTIVES

With our recent increasing understanding of the role of trained immunity in health and disease, we
are also observing a growing knowledge gap. Trained immunity is defined as a long-term enhanced
secondary effector function upon a first stimulation, but we are increasingly realizing that the un-
derlying mechanisms and subsequent secondary phenotype can differ for each stimulus or in dif-
ferent health or disease states. This might also impact the way we need to boost trained immunity
to achieve health, such as by using nonspecific effects of vaccines, or inhibit it in chronic inflam-
matory diseases. We have only begun to unravel the role of trained immunity in (inflamm)aging.
Further research is therefore warranted to study the diversity of stimuli and disease pathologies,
the accompanying intracellular metabolic and epigenetic changes that are induced, and the sub-
sequent increased inflammatory response upon secondary stimulation, in order to optimize the
therapeutic potential that trained immunity encompasses (178).
Ideal targets for designing novel approaches for therapeutics are the central mechanisms un-
derlying trained immunity, such as metabolic and epigenetic changes. Both these processes are
amenable for therapeutic targeting, as has been suggested in several reviews (178–180). Epige-
netic enzymes such as histone demethylase KDM5 and histone methyltransferase Set7 are known
to regulate trained immunity (43, 47), and Set7 is even implicated in bone marrow reprogramming
by β-glucan. These two enzymes are therefore interesting targets for preventing trained immu-
nity. Another group of potential epigenetic modifiers is bromodomain and extraterminal domain
inhibitors (BETis). BETis are increasingly recognized for their therapeutic potential in inflam-
mation (181), as they interfere with the recognition of acetylated histone marks, areas that could
well be primed by trained immunity for increased transcription upon secondary stimulation. An
example of a BETi that is under investigation is iBET151. iBET151 was shown to suppress the
immune response during a fungal infection and prevent the induction of trained immunity (182).
iBET151 was also shown to reduce chronic inflammation in rheumatoid arthritis and diabetes
(183, 184). Several other BETis are now studied for their anti-inflammatory potential. Next to
dampening the effects of trained immunity and the written epigenetic marks, it would be interest-
ing to reverse trained immunity and remove the accompanying epigenetic marks. Would simply
removing the stimulus for long enough be sufficient to reverse trained immunity and the accom-
panying epigenetic changes? Further research is much warranted to study reversal of a trained
phenotype and the enzymes that remove histone marks.
In addition to epigenetic enzymes, metabolic changes are the second interesting therapeu-
tic target in trained immunity. Even though different metabolic pathways have been described
for different trained immunity stimuli, most stimuli share the activation of the PI3K/Akt/mTOR
pathway and subsequent induction of glycolysis (Figure 2), which would therefore be an interest-
ing first target. Several small molecules have been shown to reduce glycolysis in vivo, for example
3-PO, a partial glycolysis inhibitor that can significantly reduce atherosclerosis development in an
atherosclerotic mouse model (185). Interestingly, glycolysis is not completely blocked by 3-PO,
thereby guaranteeing normal immune function of the innate immune cell when needed for fight-
ing infections. Secondly, rapamycin-loaded HDL-nanoparticles have been shown to specifically

target the Akt-mTOR pathway in cells of the innate immune system. With the use of rapamycin-
loaded HDL nanoparticles, trained immunity induced by allograft transplantation could be in-
hibited and allograft rejection was prevented (177). A similar nanoparticle approach was used
to target macrophages in an atherosclerotic mouse model. Duivenvoorden et al. (186) showed
that statin-loaded HDL nanoparticles were able to prevent plaque formation and inflammation
by specifically targeting macrophages. This corresponds with our finding that statins are able to
prevent trained immunity in vitro (54). Unfortunately, statins were unable to reverse already es-
tablished trained immunity phenotypes in patients with hypercholesterolemia (60), indicating that
reversal and prevention might need two different therapeutic approaches.
In conclusion, trained immunity is a recently described property of myeloid cells that allows
them to undergo long-term functional reprogramming upon a short interaction with a stimula-
tory agent. This interaction can either induce long-term improvement of host defense and pro-
tection against heterologous infections when induced adaptively by infections or vaccinations or
lead to an inflammatory scar when augmented inappropriately by endogenous ligands, leading

to inflammation-mediated diseases. Understanding the pathways and mechanisms that mediate
trained immunity will have the potential to improve the efficacy of vaccination on the one hand
and to provide new therapeutic targets in inflammatory and autoimmune diseases on the other
hand.
DISCLOSURE STATEMENT
M.G.N. and L.A.B.J. are scientific founders of TTxD and are owners of two patents on modulation
of trained immunity. L.A.B.J. is an SAB member of Olatec Pharmaceuticals.
ACKNOWLEDGMENTS
This work was supported by IN-CONTROL CVON grants (CVON2012-03 and CVON2018-
27 to N.P.R., M.G.N., and L.A.B.J.). S.B. is supported by the Dutch Heart Foundation (Dekker
grant 2018-T028). M.G.N. is supported by a European Research Council (ERC) Advanced Grant
(ERC 833247) and a Netherlands Organization for Scientific Research Spinoza Grant (NWO SPI
94-212). L.A.B.J. is supported by a Competitiveness Operational Program grant of the Romanian
Ministry of European Funds (HINT, ID P_37_762; MySMIS 103587). N.P.R. is recipient of a
grant of the ERA-CVD Joint Transnational Call 2018, which is supported by the Dutch Heart
Foundation ( JTC2018, project MEMORY; 2018T093).
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IY39_FrontMatter ARjats.cls March 30, 2021 15:54
Annual Review of
Immunology
Volume 39, 2021
Contents
The Habitat Filters of Microbiota-Nourishing Immunity

Brittany M. Miller and Andreas J. Bäumler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Current Concepts and Advances in Graft-Versus-Host Disease Immunology
Geoffrey R. Hill, Brian C. Betts, Victor Tkachev, Leslie S. Kean,
and Bruce R. Blazar p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p19
Cytokine Regulation and Function in T Cells
Chen Dong p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p51
The Antisocial Network: Cross Talk Between Cell Death Programs in Host
Defense
Annelise G. Snyder and Andrew Oberst p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p77
The Shaping of a B Cell Pool Maximally Responsive to Infections
Nicole Baumgarth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 103
Dendritic Cells Revisited
Mar Cabeza-Cabrerizo, Ana Cardoso, Carlos M. Minutti,
Mariana Pereira da Costa, and Caetano Reis e Sousa p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 131
Group 2 Innate Lymphoid Cells: Team Players in Regulating Asthma
Noe Rodriguez-Rodriguez, Mayuri Gogoi, and Andrew N.J. McKenzie p p p p p p p p p p p p p p p p p 167
The Ins and Outs of Central Nervous System Inflammation—Lessons
Learned from Multiple Sclerosis
Valeria Ramaglia, Olga Rojas, Ikbel Naouar, and Jennifer L. Gommerman p p p p p p p p p p p p p 199
Genetics of Pediatric Immune-Mediated Diseases and Human Immunity
Erica G. Schmitt and Megan A. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227
Microglia and Central Nervous System–Associated Macrophages—From
Origin to Disease Modulation
Marco Prinz, Takahiro Masuda, Michael A. Wheeler, and Francisco J. Quintana p p p p p p 251
Epigenetic Remodeling in Innate Immunity and Inflammation
Qian Zhang and Xuetao Cao p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 279
viii
Origins, Biology, and Diseases of Tissue Macrophages

Nehemiah Cox, Maria Pokrovskii, Rocio Vicario, and Frederic Geissmann p p p p p p p p p p p p p p 313
Transcriptional and Metabolic Control of Memory B Cells and Plasma Cells
Tyler J. Ripperger and Deepta Bhattacharya p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 345
Immunosensation: Neuroimmune Cross Talk in the Skin
Masato Tamari, Aaron M. Ver Heul, and Brian S. Kim p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 369
Mitochondrial Metabolism Regulation of T Cell–Mediated Immunity
Elizabeth M. Steinert, Karthik Vasan, and Navdeep S. Chandel p p p p p p p p p p p p p p p p p p p p p p p p p 395
Natural Killer Cells: From Innate to Adaptive Features
Adriana M. Mujal, Rebecca B. Delconte, and Joseph C. Sun p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417

Control of Immunity by the Microbiota

Eduard Ansaldo, Taylor K. Farley, and Yasmine Belkaid p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 449
Control of RNA Stability in Immunity
Shizuo Akira and Kazuhiko Maeda p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 481
Glycans in Immunologic Health and Disease
Julie Y. Zhou and Brian A. Cobb p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 511
IL-17 in the Pathogenesis of Disease: Good Intentions Gone Awry
Saikat Majumder and Mandy J. McGeachy p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 537
Tissue Homeostasis and Inflammation
Matthew L. Meizlish, Ruth A. Franklin, Xu Zhou, and Ruslan Medzhitov p p p p p p p p p p p p p 557
Insights Gained from Single-Cell Analysis of Immune Cells in the Tumor
Microenvironment
Xianwen Ren, Lei Zhang, Yuanyuan Zhang, Ziyi Li, Nathan Siemers,
and Zemin Zhang p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 583
The Innate Immune Response to Mycobacterium tuberculosis Infection
Mariëtta M. Ravesloot-Chávez, Erik Van Dis, and Sarah A. Stanley p p p p p p p p p p p p p p p p p p p 611
Immune System Investigation Using Parasitic Helminths
Bonnie Douglas, Oyebola Oyesola, Martha M. Cooper, Avery Posey,
Elia Tait Wojno, Paul R. Giacomin, and De’Broski R. Herbert p p p p p p p p p p p p p p p p p p p p p p p p 639
Trained Immunity: Reprogramming Innate Immunity in Health and Disease
Siroon Bekkering, Jorge Domínguez-Andrés, Leo A.B. Joosten,
Niels P. Riksen, and Mihai G. Netea p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 667
Production and Function of Immunoglobulin A
Timothy W. Hand and Andrea Reboldi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 695
Contents ix
Eosinophil Knockout Humans: Uncovering the Role of Eosinophils

Through Eosinophil-Directed Biological Therapies
Elizabeth A. Jacobsen, David J. Jackson, Enrico Heffler, Sameer K. Mathur,
Albert J. Bredenoord, Ian D. Pavord, Praveen Akuthota,
Florence Roufosse, and Marc E. Rothenberg p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 719
Dendritic Cell Regulation of T Helper Cells
Xiangyun Yin, Shuting Chen, and Stephanie C. Eisenbarth p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 759
Decoding Cell Death: From a Veritable Library of Babel to Vade Mecum?
Lindsey D. Hughes, Yaqiu Wang, Alexandre P. Meli, Carla V. Rothlin,
and Sourav Ghosh p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 791
Indexes
Cumulative Index of Contributing Authors, Volumes 29–39 p p p p p p p p p p p p p p p p p p p p p p p p p p p 819
Cumulative Index of Article Titles, Volumes 29–39 p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 826
Errata
An online log of corrections to Annual Review of Immunology articles may be found at
http://www.annualreviews.org/errata/immunol
x Contents

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Annual Review of Immunology

Siroon Bekkering,1 Jorge Domínguez-Andrés,1

Annu. Rev. Immunol. 2021. 39:667–93 Keywords

TRAINED IMMUNITY VERSUS TOLERANCE

668 Bekkering et al.

www.annualreviews.org • Trained Immunity 669

Inducers of Trained Immunity

MECHANISMS OF TRAINED IMMUNITY

Metabolic Changes Underlying Trained Immunity

670 Bekkering et al.

Lactate Akt IGF1R

Glycolysis HIF1α mTOR

www.annualreviews.org • Trained Immunity 671

672 Bekkering et al.

Trained immunity is dependent on distinct epigenetic programs. Due to a first encounter

REPROGRAMMING OF HEMATOPOIETIC PROGENITOR CELLS

www.annualreviews.org • Trained Immunity 673

CENTRAL VERSUS PERIPHERAL INDUCTION

674 Bekkering et al.

Central trained immunity

www.annualreviews.org • Trained Immunity 675

TRAINED IMMUNITY IN NONIMMUNE CELLS

676 Bekkering et al.

TRAINED IMMUNITY IN HEALTH AND DISEASE

Protection Against Reinfection

effects of trained imm

678 Bekkering et al.

Trained Immunity Against SARS-CoV-2 Infection?

Trained Immunity in Cancer

www.annualreviews.org • Trained Immunity 679

680 Bekkering et al.

Autoinflammatory and Allergic Diseases

www.annualreviews.org • Trained Immunity 681

682 Bekkering et al.

CLINICAL IMPLICATIONS AND FUTURE PERSPECTIVES

www.annualreviews.org • Trained Immunity 683

lead to an inflammatory scar when augmented inappropriately by endogenous ligands, leading

684 Bekkering et al.

monocytes. PNAS 109(43):17537–42

www.annualreviews.org • Trained Immunity 685

programming protects newborn infants from sepsis. Nat. Immunol. 18(6):622–32

marks and establishes transcriptional memory. PNAS 115(39):E9162–71

686 Bekkering et al.

www.annualreviews.org • Trained Immunity 687

688 Bekkering et al.

www.annualreviews.org • Trained Immunity 689

690 Bekkering et al.

www.annualreviews.org • Trained Immunity 691

692 Bekkering et al.

www.annualreviews.org • Trained Immunity 693

Volume 39, 2021

The Habitat Filters of Microbiota-Nourishing Immunity

Origins, Biology, and Diseases of Tissue Macrophages

Adriana M. Mujal, Rebecca B. Delconte, and Joseph C. Sun p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 417

Control of Immunity by the Microbiota

Eosinophil Knockout Humans: Uncovering the Role of Eosinophils

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