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ScienceDirect Innate immune memory: towards a better understanding of host defense mechanisms Jessica Quintin, Shih-Chin Cheng, Jos WM van der Meer and Mihai G Netea Innate immunity is classically defined as unable to build up immunological memory. Recently however, the assumption of the lack of immunological memory within innate immune responses has been reconsidered. Plants and invertebrates lacking adaptive immune system can be protected against secondary infections. It has been shown that mammals can build cross-protection to secondary infections independently of T-lymphocytes and B-lymphocytes. Moreover, recent studies have demonstrated that innate immune cells such as NK cells and monocytes can display adaptive characteristics, a novel concept for which the term trained immunity has been proposed. Several mechanisms are involved in mediating innate immune memory, among which epigenetic histone modifications and modulation of recognition receptors on the surface of innate immune cells are likely to play a central role. Addresses Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands Corresponding author: Netea, Mihai G ([email protected])
Current Opinion in Immunology 2014, 29:1–7 This review comes from a themed issue on Host pathogens Edited by Yasmine Belkaid and Philippe Gros
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Introduction The immune host defense mechanisms are essential for fighting invading pathogens, and thus for the survival of all multicellular organisms. Immune responses have been classically divided into innate and adaptive. The cells of the innate immune system such as granulocytes, macrophages or Natural Killer (NK) cells are immediately available to fight efficiently and kill a broad range of pathogens, but are thought not to confer specificity or immunological memory to the host defense. In contrast, the specific (or adaptive) immune responses, such as the production of antibodies or the generation of specific T cell clones, confer specificity towards antigens [1] and often lifelong protection to re-infection with the same www.sciencedirect.com
pathogen through the rapid clonal expansion of memory T and/or B cells [2]. The specificity to the response against a particular pathogen and immunological memory are believed to be the main features that distinguish adaptive (lymphocyte-mediated) from innate (phagocyte-mediated) immunity. The last few years of research have dramatically changed the dogma of innate immunity being non-specific. Indeed, the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), and RigI-helicases present on leukocytes surface are responsible for the semi-specific activation of cells of the innate immunity through the specific recognition of conserved microbial molecules called pathogen-associated molecular patterns (PAMPs) [3]. Moreover, in addition to providing early defense against infections, innate immune responses play an essential role in triggering and driving the acquired immune system to respond effectively to infection [4]. More recent studies have also proposed to revise our perspective on the dichotomy of the immune system in terms of immunological memory. Indeed, innate immunity that characterize plants bear memory features following an initial infection [5]. Such innate memory characteristics have also been described in invertebrates [6,7]. Finally, recent observations in vertebrates indicate that innate immune cells could present characteristics of immunological memory as well (for review see [8,9]). In addition to that, recent studies have shown the ability of macrophages to profoundly reprogram their function during and after an infection, which blurs the distinction between innate and adaptive responses [10]. Detection of microbial patterns by phagocytes during the course of infection not only permits the activation of the cells but also results in the change of the expression of receptors on the surface of macrophages and NK cells. Therefore, similarly to the acquired tailored immune response, upon exposure to a microorganism or a microbial ligand, macrophages are capable to adapt and to reshape their response to a subsequent microbial assault. This feature has been defined as the ‘adaptive’ form of the innate immunity [11,12]. Recently, we have proposed the term ‘trained immunity’ to describe the enhanced innate host defense when a second infection occurs [8,13]. Trained immunity is expressed as protection against reinfection by the same or different Current Opinion in Immunology 2014, 29:1–7
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The discovery of memory characteristics of prototypic innate immune cells such as NK cells or monocytes represents a paradigm shift in immunity [11,19,20]. In the present review we detail the characteristics of trained immunity, its differences from classic lymphocyte-dependent adaptive immunological memory, and we will underline the current advances in understanding the mechanisms involved.
Trained immunity A reappraisal of relatively old studies performed in mice that have been vaccinated with the anti-tuberculosis vaccine BCG shows that this vaccination protects not only against mycobacteria, but also against secondary infections with Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, Candida albicans or Schistosoma mansoni [21–24]. Interestingly, the non-specific BCG (Bacillus Calmette-Gue´rin) protective effect is still induced in mice deficient in T-lymphocytes and Blymphocytes [23,25], and was attributable to activated macrophages [21,24]. In addition, in newborn children BCG vaccination has been shown to confer non-specific beneficial effects against infections other than tuberculosis, with a significant better survival in early childhood [26,27]. In addition, a significant number of reports have described that individuals vaccinated with vaccinia virus recovered quicker from other infections than smallpox, or were less susceptible to infectious diseases such as measles, scarlet fever, whooping cough and syphilis when compared to non-vaccinated persons [28]. Similar observations have been also made for vaccination with measles vaccine, which also has important non-specific protective effects [29]. As the protection against other infections reported in these studies is non-specific, it is unlikely that a specific adaptive immune response is the protective mechanism responsible, and a recent study has highlighted the role of monocytes in the non-specific conferred protection provided by BCG vaccination [18] (Figure 1). Not only epidemiological data, but also experimental studies suggest that innate immunity itself may be heightened after an initial infectious episode. Non-lethal infection with C. albicans protects mice not only towards virulent C. albicans strain, but also against the Grampositive bacteria S. aureus infection [30]. Interestingly, this Candida-induced protection could still be conferred Current Opinion in Immunology 2014, 29:1–7
Figure 1
Priming : infection/vaccination innate immune response
pathogens in organisms lacking adaptive immune responses such as plants [5] or invertebrates [6,14]. In addition, trained immunity is also an important feature of innate immunity in vertebrates, in which it provides protection in parallel with the existence of classical T/ B cell dependent adaptive responses. The beneficial effect of trained immunity during infections in vertebrates was demonstrated in mice deficient in functional T and B cells [15,16,17,18].
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Illustration the proposed model of differential programming of innate immunity. Innate immune responses during and after an infectious episode can lead to immunological programming, and a decreased/ refractory (tolerance-immunoparalysis) or heightened (trained immunity) immunity, which might translate into increased or decreased susceptibility to infections, respectively.
to mice devoid of functional T and B cells [31]. In fact, macrophages, prototypical innate immune cells, have been described as being the cells responsible for this nonspecific protection to re-infection [30,31]. Production of proinflammatory cytokines by macrophages seems mandatory [32]. Recently, we further investigated these preliminary observations and emphasized the role of the b-glucan cell component in the protection induced by C. albicans and the inherent key role played by monocytes in the non-specific protective effects mediated by bglucans [17]. In addition, recent studies demonstrate that not only bacteria and yeasts, but also viruses are capable of conferring protection to re-infection independently of the adaptive immunity. Indeed, during viral latency, herpesvirus can confer a beneficial protection against the bacterial pathogens L. monocytogenes and Yersinia pestis, due to the upregulation of the basal level of innate immunity such as macrophage activation, as well as heightened TNFa and IFNg production [33]. Strikingly, this protection requires IFNg but does not require the effector functions of (CD4+ and CD8+) lymphocytes at the time of the second infection. The seminal studies by Mackaness almost half a century ago have suggested that macrophages are the mediators of the latency protection and the durability of this protection, lasting after clearance of the viral acute infection, actually distinguish the latency-induced cross-protection from the classical crossprotection [34]. Noteworthy, the purified TLR9 ligand CpG ODN can also mediate protection against Leishmania [35] and L. monocytogenes infections [36] that persists for at least two weeks and is accompanied by a sustained expression of the cytokine IL-12. Remarkably, the www.sciencedirect.com
Trained immunity as host defense mechanisms Quintin et al.
protection conferred to primates against Leishmania infection is reproducible in retrovirus-infected primates [35]. In addition, several ground-breaking studies in mammals have defined memory characteristics for the NK cells. Cytokine-activated NK cells transferred into naive hosts can be specifically detected 7–22 days after transfer, are phenotypically similar to naive cells and are not constitutively producing IFNg. However, they produce significantly more IFNg when restimulated. This memory-like property is intrinsic to the NK cell [37]. Likewise, infection of mice with cytomegalovirus leads to NK cell proliferation, followed by a contraction phase at the end of the infection, and long-time survival of primed NK cells in lymphoid organs for several months. These ‘memory’ NK cells can rapidly degranulate and produce cytokines upon reactivation, conferring protective immunity in an adoptive transfer model [15]. Similarly, long-lived NK cells after hapten sensitization are responsible for contact hypersensitivity response, independently of B and T lymphocytes [38].
Molecular mechanisms of trained immunity Taken together, the studies reviewed above demonstrate that innate immune responses in mammals have the capacity to be ‘primed’ or ‘trained’, and thus exert a new type of immunological memory upon re-infection, proposed to be called trained immunity [8,13]. Plants are devoid of adaptive immune system and lack the ‘classical’ mobile immune cells such as phagocytes or lymphocytes that represent the cornerstone of animal immunity. The plant host defense mechanisms are thus mediated by effective local immune response, in addition to effectors such as salicylic acid, jasmonate, ethylene or nitric oxide [39]. These soluble mediators are expressed in plants in response to infection and are true signaling molecules that permit to mount and spread an efficient defense throughout the plant tissues. The mechanisms have been defined as systemic acquired resistance (SAR) and induced systemic resistance (ISR), depending on the nature of the elicitor and the regulatory pathways involved [40]. Upon re-infection, SAR and ISR permit to develop a strengthened response, irrespective of the pathogen encountered. This conferred resistance is long lasting, sometimes for the entire lifetime of the plant, and represents an immunological memory of past infectious insults. During the past two decades research in the field has permitted to define some of the mechanisms underlying the induced-resistance systems and several excellent reviews are available [5,40]. Recent evidence suggests that SAR plant immunity involves regulation by chromatin remodeling and DNA methylation and that SAR transmission on to progeny through seeds is mediated by epigenetic regulation at the level of the H3K9 acetylation [41,42]. www.sciencedirect.com
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In mammals, innate immune memory was for the first time described decades ago, reported as being independent of T or B cells and attributable to activated macrophages. But it is only recently that a more in-depth approach of the trained immune memory has enabled the discovery of potential molecular mechanisms. NK cell mediated memory upon cytomegalovirus challenge is dependent on the expression of the virus-specific Ly49H receptor, or NKG2C in human, leading to the recruitment of Syk and SAP70 [15], whereas the haptenmediated memory of NK cells requires the chemokine receptor CXCR6 [16]. Yet, the molecular mechanisms of NK cell memory are to be described, and in that respect the coming years promise to provide exciting new knowledge. Modulation of monocyte and macrophage function is a crucial component of our host immune response, and recent studies have shown that they can also display adaptive characteristics. A primary contact of monocytes and macrophages with high concentrations of LPS or other microbial ligands, such as occurs in sepsis, will drive them in a tolerant state during which they are refractory to secondary stimulations. Interestingly however, ultra-low LPS has been reported to trigger the opposite effect: they prime monocytes towards an enhanced inflammatory response to subsequent endotoxin challenge [43]. Recent advances in the field propose that this upregulation of inflammatory effectors acts through IRAK1 kinase, selectively inducing enhancerbinding protein C/EBP@, while keeping the nuclear factor NFkB in an inactivate state [43]. Additional studies have shown that modulation of pattern recognition receptors expression is also involved in the adaptive characteristics of monocytes and macrophages, a mechanism similar to the role of membrane receptors in NK cells. More specifically, lectin receptors such as pantraxin-3, MARCO and dectin-1 have been proposed to play a role in modulating the adaptive properties of macrophages [11]. Earlier studies have reported that epigenetic programming is central to the induction of immune tolerance in monocytes. LPS-induced, TNF-induced and sepsisinduced tolerance is governed by chromatin modification and accessibility, more specifically at the level of H3K4me3, H3K27me2 and histone methyltransferase complexes [44–46]. Important new insights in the LPSdependent mediated macrophages responses shows that most of the epigenetic marks induced in the first hours of an acute LPS response fade in time. However, some of these marks do not return to a basal state when stimulation ceased. Ostuni and colleagues described a new enhancer class that they coined ‘latent enhancer’ to highlight the notion that they are inactive, unbound, and unmarked in the basal state, being selectively unveiled by stimulation [47]. While both histone methylation and acetylation occur during cell stimulation and gene Current Opinion in Immunology 2014, 29:1–7
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transcription, acetylation of histones disappear after removal of the stimulus. H3K4 monomethylation persists and represents the cornerstone of latent enhancers. Once unveiled by LPS stimulation, these latent enhancers associated with a steady H3K4me1 mark persist for 24 hours and mediate a faster and stronger response upon restimulation (Figure 2).
requires the C-type lectin receptor dectin-1 and the noncanonical Raf-1 pathway [17] whereas the non-specific protection associated with BCG vaccination/training is induced through NOD2 recognition of peptidoglycans [18]. In vivo, training of both human and murine monocytes/macrophages were associated with enhanced H3K4me3 levels. A more in-depth in vitro approach has enabled us to demonstrate that training of monocytes by C. albicans/b-glucan is maintained for at least 7 days and mediated by epigenetic reprogramming through genome-wide changes in histone trimethylation at
Recently we described the importance of epigenetic programming for trained immunity. C. albicans and b-glucan-dependent functional reprogramming of monocytes
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Current model of differential immune programming through epigenetic imprinting. Monocytes or macrophages that have never seen a first encounter/ stimulation are in a naive state, and so are their promoters and enhancers. Upon a first stimulation, enhancers are within few hours rapidly marked with H3K4me1 often together with H3K27ac [47]. Once the first stimulus is washed-out, H3K27ac marks are lost but some enhancers, the latent enhancers remain associated with H3K4me1 [47]. Similarly, after 24 hours of a first stimulation, increase in H3K4me3 at the level of some promoters can also be observed [17]. Whether H3K4me3 could be detected earlier in the course of infection remains to be established. Interestingly, the H3K4me1 mark at enhancers or H3K4me3 at promoters could still be observed up to 5 days after the first stimuli was waned [17,47]. As a result of the initial stimulation and reminiscent epigenetic mark, primed (24 hours after stimulation) or trained (6 days after stimulation) mononuclear phagocytes can respond more strongly to different type of secondary stimulation: transcription factors are more rapidly activated (in primed cells) and can produce an enhanced pro-inflammatory response compared to control cells [17,47]. Current Opinion in Immunology 2014, 29:1–7
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Trained immunity as host defense mechanisms Quintin et al.
H3K4, but not at H3K27 level. These genome-wide modifications in H3K4me3 correlate with changes in gene (transcripts) expression. Of interest, the H3K4me3 signature noted on day 7 samples is already apparent after 24 hours of b-glucan incubation and H3K4me3 patterns do not diminish after 7 days when compared to 24 hours. These recent observations indicate that a stable epigenetic program in monocytes could be maintained for at least a week, and possible longer. Whereas other commensal microorganisms of the bacterial or viral phyla can induce such functional reprogramming remains to be studied. In line with this, a very recent report suggests that depending on the type of bacterial or viral ligands they encountered, monocytes are functionally programmed for either an enhanced (training) or a decreased (tolerance) cytokine production, a function mediated by both histone methylation and acetylation [48]. To conclude, epigenetic mechanisms are most likely one of the cornerstones of innate immune memory. The mechanisms governing the functional fate of the innate immune cells upon the encounter of a first microbial ligand, towards either trained immunity or tolerogenic response, are still largely unexplored, with existing research focusing on the recognition receptors and signaling cascades. More studies are needed in order to fulfill this gap in the knowledge.
Innate immune memory: conclusions and future prospects An increasing amount of evidence has been accumulated demonstrating that innate immune responses display adaptive characteristics, which are functionally equivalent to immunological memory [8,13]. The demonstration that innate immune memory is a component of the normal host defense in vertebrates changes the paradigm that divides the immune response into two separate entities: innate and adaptive immune responses. Rather than divided between two distinct components with different functions, this new concept reveals the host defense as an integrated continuum between phagocytes, innate lymphoid populations (such as NK cells) and lymphocytes within an unified terminology [49]. NK cells and monocytes have emerged as the main cell populations mediating innate immune memory in mammals. NK cells reservoir has been described in liver and spleen, providing a subset of cells for further recall response. However, the three months long-lasting in vivo memory phenotype of monocytes is puzzling [18], considering their short half-life in circulation. It is therefore tempting to hypothesize that, similarly to NK-memory cells, a reservoir of trained monocytes exists, allowing them to be periodically recruited back into the circulation, long after the original vaccination has waned. Alternatively, trained immunity may be mediated by soluble mediators that can also reprogram the monocyte precursors in the www.sciencedirect.com
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bone marrow, and those would be the source of monocytes with a primed phenotype. This area is one of the most important for future studies in trained immunity. Epigenetic programming is likely to have a central place in the mechanisms leading to innate immune memory. At this moment we can only speculate however about the molecular and signaling mechanisms that lead to histone modification during the process of trained immunity. Recently, glucose cellular metabolism has been shown to be crucial for acute immune response and studies have shown that a switch from oxidative phosphorylation to aerobic glycolysis is a crucial characteristic of activated macrophages, dendritic cells and Th1/Th17 lymphocytes [50]. Interestingly, many metabolites of glycolysis and oxidative phosphorylation are also co-factors for epigenetic enzymes [51], and it is tempting to hypothesize that metabolism switch might control epigenetic changes at the level of histones. With this respect, recent studies using a human monocyte model of endotoxin tolerance and human leukocytes from acute systemic inflammation with sepsis have reported that the deacetylase sirtuin-1 coordinates the epigenetic and bioenergy shifts at the promoters of TNFa and IL1b, a binding that was dependent on its cofactor, the NAD+ metabolites [52]. More specifically, the acute response of monocyte to lipopolysaccharide (LPS) is characterized by glycolysis [53], the response at later time points shows a switch to oxidative phosphorylation, process that subsequently induces immune tolerance by activation of sirtuin-1 and sirtuin-6 histone deacetylases [54]. The detailed study of the metabolic changes associated with both training and tolerance of innate immune cells in the coming years will assuredly unravel further the mechanisms of innate immune memory. In conclusion, innate immune memory (trained immunity) is an important component of host defense, and its discovery heralds a new step in our understanding of the interaction between innate and adaptive immune responses. The challenge for the coming years will be to combine the understanding of its role in host defense with the employment of its modulation for therapeutic targets.
Acknowledgements JQ and MGN were supported by a Vici Grant of the Netherlands Organization for Scientific Research (to MGN).
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ScienceDirect Innate immune memory: towards a better understanding of host defense mechanisms Jessica Quintin, Shih-Chin Cheng, Jos WM van der Meer and Mihai G Netea Innate immunity is classically defined as unable to build up immunological memory. Recently however, the assumption of the lack of immunological memory within innate immune responses has been reconsidered. Plants and invertebrates lacking adaptive immune system can be protected against secondary infections. It has been shown that mammals can build cross-protection to secondary infections independently of T-lymphocytes and B-lymphocytes. Moreover, recent studies have demonstrated that innate immune cells such as NK cells and monocytes can display adaptive characteristics, a novel concept for which the term trained immunity has been proposed. Several mechanisms are involved in mediating innate immune memory, among which epigenetic histone modifications and modulation of recognition receptors on the surface of innate immune cells are likely to play a central role. Addresses Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands Corresponding author: Netea, Mihai G ([email protected])
Current Opinion in Immunology 2014, 29:1–7 This review comes from a themed issue on Host pathogens Edited by Yasmine Belkaid and Philippe Gros
Available online XXX 0952-7915/$ – see front matter, # 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.coi.2014.02.006
Introduction The immune host defense mechanisms are essential for fighting invading pathogens, and thus for the survival of all multicellular organisms. Immune responses have been classically divided into innate and adaptive. The cells of the innate immune system such as granulocytes, macrophages or Natural Killer (NK) cells are immediately available to fight efficiently and kill a broad range of pathogens, but are thought not to confer specificity or immunological memory to the host defense. In contrast, the specific (or adaptive) immune responses, such as the production of antibodies or the generation of specific T cell clones, confer specificity towards antigens [1] and often lifelong protection to re-infection with the same www.sciencedirect.com
pathogen through the rapid clonal expansion of memory T and/or B cells [2]. The specificity to the response against a particular pathogen and immunological memory are believed to be the main features that distinguish adaptive (lymphocyte-mediated) from innate (phagocyte-mediated) immunity. The last few years of research have dramatically changed the dogma of innate immunity being non-specific. Indeed, the pattern recognition receptors (PRRs) such as the Toll-like receptors (TLRs), C-type lectin receptors (CLRs), NOD-like receptors (NLRs), and RigI-helicases present on leukocytes surface are responsible for the semi-specific activation of cells of the innate immunity through the specific recognition of conserved microbial molecules called pathogen-associated molecular patterns (PAMPs) [3]. Moreover, in addition to providing early defense against infections, innate immune responses play an essential role in triggering and driving the acquired immune system to respond effectively to infection [4]. More recent studies have also proposed to revise our perspective on the dichotomy of the immune system in terms of immunological memory. Indeed, innate immunity that characterize plants bear memory features following an initial infection [5]. Such innate memory characteristics have also been described in invertebrates [6,7]. Finally, recent observations in vertebrates indicate that innate immune cells could present characteristics of immunological memory as well (for review see [8,9]). In addition to that, recent studies have shown the ability of macrophages to profoundly reprogram their function during and after an infection, which blurs the distinction between innate and adaptive responses [10]. Detection of microbial patterns by phagocytes during the course of infection not only permits the activation of the cells but also results in the change of the expression of receptors on the surface of macrophages and NK cells. Therefore, similarly to the acquired tailored immune response, upon exposure to a microorganism or a microbial ligand, macrophages are capable to adapt and to reshape their response to a subsequent microbial assault. This feature has been defined as the ‘adaptive’ form of the innate immunity [11,12]. Recently, we have proposed the term ‘trained immunity’ to describe the enhanced innate host defense when a second infection occurs [8,13]. Trained immunity is expressed as protection against reinfection by the same or different Current Opinion in Immunology 2014, 29:1–7
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The discovery of memory characteristics of prototypic innate immune cells such as NK cells or monocytes represents a paradigm shift in immunity [11,19,20]. In the present review we detail the characteristics of trained immunity, its differences from classic lymphocyte-dependent adaptive immunological memory, and we will underline the current advances in understanding the mechanisms involved.
Trained immunity A reappraisal of relatively old studies performed in mice that have been vaccinated with the anti-tuberculosis vaccine BCG shows that this vaccination protects not only against mycobacteria, but also against secondary infections with Listeria monocytogenes, Salmonella typhimurium, Staphylococcus aureus, Candida albicans or Schistosoma mansoni [21–24]. Interestingly, the non-specific BCG (Bacillus Calmette-Gue´rin) protective effect is still induced in mice deficient in T-lymphocytes and Blymphocytes [23,25], and was attributable to activated macrophages [21,24]. In addition, in newborn children BCG vaccination has been shown to confer non-specific beneficial effects against infections other than tuberculosis, with a significant better survival in early childhood [26,27]. In addition, a significant number of reports have described that individuals vaccinated with vaccinia virus recovered quicker from other infections than smallpox, or were less susceptible to infectious diseases such as measles, scarlet fever, whooping cough and syphilis when compared to non-vaccinated persons [28]. Similar observations have been also made for vaccination with measles vaccine, which also has important non-specific protective effects [29]. As the protection against other infections reported in these studies is non-specific, it is unlikely that a specific adaptive immune response is the protective mechanism responsible, and a recent study has highlighted the role of monocytes in the non-specific conferred protection provided by BCG vaccination [18] (Figure 1). Not only epidemiological data, but also experimental studies suggest that innate immunity itself may be heightened after an initial infectious episode. Non-lethal infection with C. albicans protects mice not only towards virulent C. albicans strain, but also against the Grampositive bacteria S. aureus infection [30]. Interestingly, this Candida-induced protection could still be conferred Current Opinion in Immunology 2014, 29:1–7
Figure 1
Priming : infection/vaccination innate immune response
pathogens in organisms lacking adaptive immune responses such as plants [5] or invertebrates [6,14]. In addition, trained immunity is also an important feature of innate immunity in vertebrates, in which it provides protection in parallel with the existence of classical T/ B cell dependent adaptive responses. The beneficial effect of trained immunity during infections in vertebrates was demonstrated in mice deficient in functional T and B cells [15,16,17,18].
Training
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Illustration the proposed model of differential programming of innate immunity. Innate immune responses during and after an infectious episode can lead to immunological programming, and a decreased/ refractory (tolerance-immunoparalysis) or heightened (trained immunity) immunity, which might translate into increased or decreased susceptibility to infections, respectively.
to mice devoid of functional T and B cells [31]. In fact, macrophages, prototypical innate immune cells, have been described as being the cells responsible for this nonspecific protection to re-infection [30,31]. Production of proinflammatory cytokines by macrophages seems mandatory [32]. Recently, we further investigated these preliminary observations and emphasized the role of the b-glucan cell component in the protection induced by C. albicans and the inherent key role played by monocytes in the non-specific protective effects mediated by bglucans [17]. In addition, recent studies demonstrate that not only bacteria and yeasts, but also viruses are capable of conferring protection to re-infection independently of the adaptive immunity. Indeed, during viral latency, herpesvirus can confer a beneficial protection against the bacterial pathogens L. monocytogenes and Yersinia pestis, due to the upregulation of the basal level of innate immunity such as macrophage activation, as well as heightened TNFa and IFNg production [33]. Strikingly, this protection requires IFNg but does not require the effector functions of (CD4+ and CD8+) lymphocytes at the time of the second infection. The seminal studies by Mackaness almost half a century ago have suggested that macrophages are the mediators of the latency protection and the durability of this protection, lasting after clearance of the viral acute infection, actually distinguish the latency-induced cross-protection from the classical crossprotection [34]. Noteworthy, the purified TLR9 ligand CpG ODN can also mediate protection against Leishmania [35] and L. monocytogenes infections [36] that persists for at least two weeks and is accompanied by a sustained expression of the cytokine IL-12. Remarkably, the www.sciencedirect.com
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protection conferred to primates against Leishmania infection is reproducible in retrovirus-infected primates [35]. In addition, several ground-breaking studies in mammals have defined memory characteristics for the NK cells. Cytokine-activated NK cells transferred into naive hosts can be specifically detected 7–22 days after transfer, are phenotypically similar to naive cells and are not constitutively producing IFNg. However, they produce significantly more IFNg when restimulated. This memory-like property is intrinsic to the NK cell [37]. Likewise, infection of mice with cytomegalovirus leads to NK cell proliferation, followed by a contraction phase at the end of the infection, and long-time survival of primed NK cells in lymphoid organs for several months. These ‘memory’ NK cells can rapidly degranulate and produce cytokines upon reactivation, conferring protective immunity in an adoptive transfer model [15]. Similarly, long-lived NK cells after hapten sensitization are responsible for contact hypersensitivity response, independently of B and T lymphocytes [38].
Molecular mechanisms of trained immunity Taken together, the studies reviewed above demonstrate that innate immune responses in mammals have the capacity to be ‘primed’ or ‘trained’, and thus exert a new type of immunological memory upon re-infection, proposed to be called trained immunity [8,13]. Plants are devoid of adaptive immune system and lack the ‘classical’ mobile immune cells such as phagocytes or lymphocytes that represent the cornerstone of animal immunity. The plant host defense mechanisms are thus mediated by effective local immune response, in addition to effectors such as salicylic acid, jasmonate, ethylene or nitric oxide [39]. These soluble mediators are expressed in plants in response to infection and are true signaling molecules that permit to mount and spread an efficient defense throughout the plant tissues. The mechanisms have been defined as systemic acquired resistance (SAR) and induced systemic resistance (ISR), depending on the nature of the elicitor and the regulatory pathways involved [40]. Upon re-infection, SAR and ISR permit to develop a strengthened response, irrespective of the pathogen encountered. This conferred resistance is long lasting, sometimes for the entire lifetime of the plant, and represents an immunological memory of past infectious insults. During the past two decades research in the field has permitted to define some of the mechanisms underlying the induced-resistance systems and several excellent reviews are available [5,40]. Recent evidence suggests that SAR plant immunity involves regulation by chromatin remodeling and DNA methylation and that SAR transmission on to progeny through seeds is mediated by epigenetic regulation at the level of the H3K9 acetylation [41,42]. www.sciencedirect.com
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In mammals, innate immune memory was for the first time described decades ago, reported as being independent of T or B cells and attributable to activated macrophages. But it is only recently that a more in-depth approach of the trained immune memory has enabled the discovery of potential molecular mechanisms. NK cell mediated memory upon cytomegalovirus challenge is dependent on the expression of the virus-specific Ly49H receptor, or NKG2C in human, leading to the recruitment of Syk and SAP70 [15], whereas the haptenmediated memory of NK cells requires the chemokine receptor CXCR6 [16]. Yet, the molecular mechanisms of NK cell memory are to be described, and in that respect the coming years promise to provide exciting new knowledge. Modulation of monocyte and macrophage function is a crucial component of our host immune response, and recent studies have shown that they can also display adaptive characteristics. A primary contact of monocytes and macrophages with high concentrations of LPS or other microbial ligands, such as occurs in sepsis, will drive them in a tolerant state during which they are refractory to secondary stimulations. Interestingly however, ultra-low LPS has been reported to trigger the opposite effect: they prime monocytes towards an enhanced inflammatory response to subsequent endotoxin challenge [43]. Recent advances in the field propose that this upregulation of inflammatory effectors acts through IRAK1 kinase, selectively inducing enhancerbinding protein C/EBP@, while keeping the nuclear factor NFkB in an inactivate state [43]. Additional studies have shown that modulation of pattern recognition receptors expression is also involved in the adaptive characteristics of monocytes and macrophages, a mechanism similar to the role of membrane receptors in NK cells. More specifically, lectin receptors such as pantraxin-3, MARCO and dectin-1 have been proposed to play a role in modulating the adaptive properties of macrophages [11]. Earlier studies have reported that epigenetic programming is central to the induction of immune tolerance in monocytes. LPS-induced, TNF-induced and sepsisinduced tolerance is governed by chromatin modification and accessibility, more specifically at the level of H3K4me3, H3K27me2 and histone methyltransferase complexes [44–46]. Important new insights in the LPSdependent mediated macrophages responses shows that most of the epigenetic marks induced in the first hours of an acute LPS response fade in time. However, some of these marks do not return to a basal state when stimulation ceased. Ostuni and colleagues described a new enhancer class that they coined ‘latent enhancer’ to highlight the notion that they are inactive, unbound, and unmarked in the basal state, being selectively unveiled by stimulation [47]. While both histone methylation and acetylation occur during cell stimulation and gene Current Opinion in Immunology 2014, 29:1–7
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transcription, acetylation of histones disappear after removal of the stimulus. H3K4 monomethylation persists and represents the cornerstone of latent enhancers. Once unveiled by LPS stimulation, these latent enhancers associated with a steady H3K4me1 mark persist for 24 hours and mediate a faster and stronger response upon restimulation (Figure 2).
requires the C-type lectin receptor dectin-1 and the noncanonical Raf-1 pathway [17] whereas the non-specific protection associated with BCG vaccination/training is induced through NOD2 recognition of peptidoglycans [18]. In vivo, training of both human and murine monocytes/macrophages were associated with enhanced H3K4me3 levels. A more in-depth in vitro approach has enabled us to demonstrate that training of monocytes by C. albicans/b-glucan is maintained for at least 7 days and mediated by epigenetic reprogramming through genome-wide changes in histone trimethylation at
Recently we described the importance of epigenetic programming for trained immunity. C. albicans and b-glucan-dependent functional reprogramming of monocytes
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Naive 1st stimulation Slow activation Moderate inflammatory response
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Primed 2nd stimulation Fast activation ? high inflammatory response T=6d
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Current model of differential immune programming through epigenetic imprinting. Monocytes or macrophages that have never seen a first encounter/ stimulation are in a naive state, and so are their promoters and enhancers. Upon a first stimulation, enhancers are within few hours rapidly marked with H3K4me1 often together with H3K27ac [47]. Once the first stimulus is washed-out, H3K27ac marks are lost but some enhancers, the latent enhancers remain associated with H3K4me1 [47]. Similarly, after 24 hours of a first stimulation, increase in H3K4me3 at the level of some promoters can also be observed [17]. Whether H3K4me3 could be detected earlier in the course of infection remains to be established. Interestingly, the H3K4me1 mark at enhancers or H3K4me3 at promoters could still be observed up to 5 days after the first stimuli was waned [17,47]. As a result of the initial stimulation and reminiscent epigenetic mark, primed (24 hours after stimulation) or trained (6 days after stimulation) mononuclear phagocytes can respond more strongly to different type of secondary stimulation: transcription factors are more rapidly activated (in primed cells) and can produce an enhanced pro-inflammatory response compared to control cells [17,47]. Current Opinion in Immunology 2014, 29:1–7
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Trained immunity as host defense mechanisms Quintin et al.
H3K4, but not at H3K27 level. These genome-wide modifications in H3K4me3 correlate with changes in gene (transcripts) expression. Of interest, the H3K4me3 signature noted on day 7 samples is already apparent after 24 hours of b-glucan incubation and H3K4me3 patterns do not diminish after 7 days when compared to 24 hours. These recent observations indicate that a stable epigenetic program in monocytes could be maintained for at least a week, and possible longer. Whereas other commensal microorganisms of the bacterial or viral phyla can induce such functional reprogramming remains to be studied. In line with this, a very recent report suggests that depending on the type of bacterial or viral ligands they encountered, monocytes are functionally programmed for either an enhanced (training) or a decreased (tolerance) cytokine production, a function mediated by both histone methylation and acetylation [48]. To conclude, epigenetic mechanisms are most likely one of the cornerstones of innate immune memory. The mechanisms governing the functional fate of the innate immune cells upon the encounter of a first microbial ligand, towards either trained immunity or tolerogenic response, are still largely unexplored, with existing research focusing on the recognition receptors and signaling cascades. More studies are needed in order to fulfill this gap in the knowledge.
Innate immune memory: conclusions and future prospects An increasing amount of evidence has been accumulated demonstrating that innate immune responses display adaptive characteristics, which are functionally equivalent to immunological memory [8,13]. The demonstration that innate immune memory is a component of the normal host defense in vertebrates changes the paradigm that divides the immune response into two separate entities: innate and adaptive immune responses. Rather than divided between two distinct components with different functions, this new concept reveals the host defense as an integrated continuum between phagocytes, innate lymphoid populations (such as NK cells) and lymphocytes within an unified terminology [49]. NK cells and monocytes have emerged as the main cell populations mediating innate immune memory in mammals. NK cells reservoir has been described in liver and spleen, providing a subset of cells for further recall response. However, the three months long-lasting in vivo memory phenotype of monocytes is puzzling [18], considering their short half-life in circulation. It is therefore tempting to hypothesize that, similarly to NK-memory cells, a reservoir of trained monocytes exists, allowing them to be periodically recruited back into the circulation, long after the original vaccination has waned. Alternatively, trained immunity may be mediated by soluble mediators that can also reprogram the monocyte precursors in the www.sciencedirect.com
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bone marrow, and those would be the source of monocytes with a primed phenotype. This area is one of the most important for future studies in trained immunity. Epigenetic programming is likely to have a central place in the mechanisms leading to innate immune memory. At this moment we can only speculate however about the molecular and signaling mechanisms that lead to histone modification during the process of trained immunity. Recently, glucose cellular metabolism has been shown to be crucial for acute immune response and studies have shown that a switch from oxidative phosphorylation to aerobic glycolysis is a crucial characteristic of activated macrophages, dendritic cells and Th1/Th17 lymphocytes [50]. Interestingly, many metabolites of glycolysis and oxidative phosphorylation are also co-factors for epigenetic enzymes [51], and it is tempting to hypothesize that metabolism switch might control epigenetic changes at the level of histones. With this respect, recent studies using a human monocyte model of endotoxin tolerance and human leukocytes from acute systemic inflammation with sepsis have reported that the deacetylase sirtuin-1 coordinates the epigenetic and bioenergy shifts at the promoters of TNFa and IL1b, a binding that was dependent on its cofactor, the NAD+ metabolites [52]. More specifically, the acute response of monocyte to lipopolysaccharide (LPS) is characterized by glycolysis [53], the response at later time points shows a switch to oxidative phosphorylation, process that subsequently induces immune tolerance by activation of sirtuin-1 and sirtuin-6 histone deacetylases [54]. The detailed study of the metabolic changes associated with both training and tolerance of innate immune cells in the coming years will assuredly unravel further the mechanisms of innate immune memory. In conclusion, innate immune memory (trained immunity) is an important component of host defense, and its discovery heralds a new step in our understanding of the interaction between innate and adaptive immune responses. The challenge for the coming years will be to combine the understanding of its role in host defense with the employment of its modulation for therapeutic targets.
Acknowledgements JQ and MGN were supported by a Vici Grant of the Netherlands Organization for Scientific Research (to MGN).
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