Hematopoietic stem and progenitor cells as a reservoir for trained immunity

‘Trained immunity’, or ‘innate immune memory’, describes the concept that innate immune cells, such as macrophages (Kaufmann et al., 2018; Yao et al., 2018), neutrophils (Kalafati et al., 2020), and NK cells (Verma et al., 2017), gain enhanced function after a primary encounter with an immunological stimulus (Netea et al., 2020). While adaptive immune memory is achieved by recombination of antigen receptors followed by positive and negative selection, trained immunity is generated through epigenetic modifications and metabolic reprogramming incurred upon inflammatory stimulation (Quintin et al., 2012; Cirovic et al., 2020). Trained immunity can be induced through a variety of infections, vaccines, and adjuvants such as Bacillus Calmette–Guérin (BCG) and the fungal cell wall component beta glucan (β-glucan), or inflammatory stimuli released during autoimmune diseases. Trained immunity initiated by these stimuli can enhance cross-protective host immunity against infections or cancer (Kalafati et al., 2020; Hersh et al., 1977; van Puffelen et al., 2020; Larsen et al., 2020b; Mills et al., 2024; Walk et al., 2020). Innate immune memory has also been associated with maladaptive effects such as periodontitis, arthritis, and long COVID (Cheong et al., 2023; Christ et al., 2018, Li et al., 2022). Indeed, some attempts to use trained immunity to protect against infection have resulted in counterproductive hyperinflammation (Walk et al., 2019). Thus, while trained immunity can serve as a powerful tool to improve host immunity, it also has the capacity to confer a detrimental burden on patient health.

In humans, trained immunity after BCG vaccination was found to last for over 1 year in circulating monocytes (Kleinnijenhuis et al., 2014). These long-term effects were surprising since circulating monocytes have a half-life of only a few days in humans and mice (Patel et al., 2017; Teh et al., 2019). As circulating innate immune cells lack self-renewal capacity and are primarily short-lived, investigators have turned to hematopoietic stem and progenitor cells (HSPCs), the long-lived and self-renewing progenitors of innate immune cells (see Box 1), as the potential reservoir for trained immunity (Orkin and Zon, 2008). Possessing both multilineage differentiation potential and self-renewal capacity, HSPCs are known to respond to environmental cues such as inflammation triggered by infection, diet, or aging (King and Goodell, 2011; Takizawa et al., 2012; Pietras, 2017; Ding et al., 2021). Indeed, HSPCs express Toll-like receptors and other pathogen-associated molecular pattern recognition and cytokine receptors that equip them to detect and respond to inflammatory stimuli. Upon detection of external stressors, HSPCs undergo emergency myelopoiesis, thereby directly contributing to the immune response (Cao et al., 2024).

The potential for HSPCs to serve as a memory reservoir for trained immunity has been described in both murine (Kaufmann et al., 2018; Mills et al., 2024; Mitroulis et al., 2018; Khan et al., 2020; Kain et al., 2023; Zhu et al., 2024; Kalafati et al., 2020; de Laval et al., 2020; Table 1) and human studies (Cirovic et al., 2020; Cheong et al., 2023; Sun et al., 2024). Experiments in which memory phenotypes were transferred via HSPCs from trained donors into irradiated recipients have demonstrated the sufficiency of reprogrammed HSPCs to generate innate immune memory in circulating immune cells (Kaufmann et al., 2018; Mitroulis et al., 2018; Khan et al., 2020; Kain et al., 2023; de Laval et al., 2020). Long-term reprogramming has been observed in mouse studies of hemozoin-dependent Plasmodium infection (Zhu et al., 2024) and in longitudinal studies in humans trained with BCG vaccination (Cirovic et al., 2020; Sun et al., 2024) or long COVID (Cheong et al., 2023). Notably, innate immune memory has also been observed in non-immune cells, such as epidermal stem cells (Naik and Fuchs, 2022; Larsen et al., 2020a) and embryonic fibroblasts (Kamada et al., 2018). Like immune cells, these structural cells exhibit heightened transcriptional responses following an initial training period of inflammatory exposure and recovery. A common theme is that cells harboring ‘memory’ must either be self-renewing, long-lived, or both. At the very least, these cells must be able to survive the initial insult for the reprogramming to persist.

The mechanism by which HSPCs encode memory is the subject of intense investigation. Recent studies indicate two key findings: (1) inflammatory responses by HSPCs in the bone marrow are highly heterogeneous (Kain et al., 2023; Arts et al., 2018) and (2) epigenetic changes in response to infection affect HSPC quiescence and differentiation (Sun et al., 2024; de Laval et al., 2020; Hormaechea-Agulla et al., 2021). These observations raise the potential that inflammatory stimuli can affect innate immune function via selective activation, involving proliferation and differentiation, and epigenetic reprogramming of HSPC subsets, thereby influencing lineage fate determination and reshaping immune cell populations (Johansson et al., 2023).

Overall, the concept that HSPCs in the bone marrow, where 90% of HSPCs are found, are a long-term reservoir for innate immune memory is termed ‘central trained immunity’ to distinguish it from reprogramming in peripheral cell populations (Netea et al., 2020; Mende and Laurenti, 2021). In this review, we focus on the emerging evidence and mechanisms by which HSPCs encode long-term innate immune memory.

Hematopoietic stem cells (HSCs) are the adult stem cells responsible for lifelong production of blood, including immune cells. HSCs are positioned at the apex of the hematopoietic hierarchy and possess the highest multipotency and self-renewal potential (Figure 1, see Box 1). Transcriptional studies have demonstrated that inflammation promotes differentiation and loss of self-renewal potential of HSCs (Pietras, 2017; Matatall et al., 2014; Baldridge et al., 2010), leading to their eventual exhaustion (Matatall et al., 2016). Like monocytes and macrophages, HSCs express receptors for inflammatory cytokines and pathogen-associated molecular patterns such as LPS (Baldridge et al., 2010; Nagai et al., 2006; Essers et al., 2009). They can directly respond to these stimuli by producing more inflammatory cytokines, activating downstream inflammatory response pathways such as JAK–STAT signaling, and shifting metabolic pathways through mTOR signaling (Cheng et al., 2014; Mills et al., 2024; Kain et al., 2023; Baldridge et al., 2010). Notably, innate immune function responses like antigen presentation, specifically of MHC class II genes like H2-Ab1, can be observed in HSCs in several contexts including M. avium infection (Hormaechea-Agulla et al., 2021), LPS stimulation (Hernández-Malmierca et al., 2022), and autoimmune disease models mimicking systemic lupus erythematosus (Mills et al., 2024). Thus, despite their disparate position in the hematopoietic hierarchy, HSCs and innate immune cells share many common biological processes. This observation raises the possibility that inflammatory stimuli activate and reprogram transcription networks that are directly passed down to trained immune cell progeny.

Figure 1

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Methods to study HSC function have been developed over several decades. HSC transplantation studies in mice have been used to functionally define HSCs and study their role in various contexts, including trained immunity (Kaufmann et al., 2018; Mitroulis et al., 2018; Pietras et al., 2015; Ochando et al., 2023). While many different transplant strategies exist (Kang et al., 2024; Yeung et al., 2024; Chanut et al., 2021), the most common ones use whole body irradiation to ablate fast cycling cells, clear the hematopoietic niche, and allow for successful engraftment of donor HSPCs. Donor HSPCs injected intravenously home to the bone marrow and produce blood for a period of time that is proportionate to their self-renewal potential (Pietras et al., 2015; Al-Amoodi et al., 2022). Multipotent progenitors and committed myeloid progenitors can produce blood, particularly myeloid cells, for up to several weeks, whereas long-term engraftment beyond 3 months is maintained by long-term HSCs (LT-HSCs) (Säwen et al., 2018; Oguro et al., 2013; Spangrude et al., 1988; Figure 2). This observation has led some to conclude that LT-HSCs must be the reservoir for long-term central trained immunity; however, our own work transplanting M. avium-trained LT-HSCs suggests LT-HSCs alone cannot confer central trained immunity-mediated host protection (Kain et al., 2023). In addition, studies of native hematopoiesis in the absence of transplantation have indicated a significant long-term contribution of multipotent progenitors to hematopoiesis (Sun et al., 2014; Busch and Rodewald, 2016; Pei et al., 2017; Cheng et al., 2020). This raises the possibility that multipotent progenitors may play a key role in central trained immunity. New in vitro culture methods like polyvinyl alcohol culturing of HSCs and/or downstream progenitors will enable researchers to assess the durability and relevance of epigenetic reprogramming in specific HSPC subpopulations (Wilkinson et al., 2019).

Figure 2

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Transplant models typically involve pre-conditioning regimens such as irradiation or chemotherapy to enable engraftment of transplanted cells (Hasan et al., 2024). These harsh regimens induce systemic inflammation, immune cell activation, and disruption of the bone marrow niche, thereby introducing confounding variables to studies (Mitroulis et al., 2018). Transplant models also reduce the capacity to study contributions by MPPs or other progenitors which may be long-lived in native hematopoiesis but not after transplant, as mentioned above. While transplant models remain invaluable for addressing questions of cellular origin and lineage tracing, non-transplant approaches provide complementary insights by focusing on the intrinsic properties of HSPCs within a physiologically intact niche, offering a reproducible framework for studying trained immunity (Netea et al., 2020; Bloom et al., 2023).

Compared to LT-HSCs, ST-HSCs, and MPPs are thought to have a more limited lifespan of less than 6 months and typically contribute more transiently to hematopoiesis, rapidly cycling to replenish downstream progenitor populations (Sun et al., 2014; Busch and Rodewald, 2016; Pei et al., 2017; Cheng et al., 2020; Ema et al., 2014). ST-HSCs and MPPs retain multipotency, a high proliferation potential compared to LT-HSCs, and a strong commitment to lineage differentiation, serving as critical intermediates that amplify cell numbers and ensure robust generation of lineage-restricted progenitors, thereby supporting the rapid production of fully differentiated immune cells (Höfer and Rodewald, 2018). MPP2, MPP3, and MPP4 exhibit distinct lineage biases, with MPP2 favoring megakaryocytic/erythroid differentiation, MPP3 displaying a myeloid bias, and MPP4 predominantly contributing to lymphoid lineages (see Box 1; Pietras et al., 2015; Kang et al., 2023). Unlike LT-HSCs, ST-HSCs, and MPPs do not sustain hematopoiesis over extended periods of time following transplantation, making it difficult to study the contribution of these cells in transplant models.

Several non-transplant studies reveal a possible role for ST-HSCs and MPPs in central trained immunity. Conserved transcriptional and epigenetic alterations, including upregulation of C/EBPβ, increased chromatin accessibility at innate immunity genes marked by H3K4me3 (de Laval et al., 2020), and metabolic reprogramming toward enhanced glycolysis Mills et al., 2024 have been shown to occur in LT-HSCs that confer trained immunity in transplant models. These same transcriptional and epigenetic alterations are conserved in the ST-HSC and MPP compartments of recipients of trained LT-HSCs, suggesting that these cells may act as potent producers of innate immune memory effector cells. Following the induction of innate immune training with BCG vaccination or the fungal cell wall component β-glucan, ST-HSCs and MPPs exhibited enhanced expression of gene sets involved in DNA replication and cell division, as well as upregulation of several myeloid-lineage transcription factors at the expense of lymphoid-lineage TFs, indicating a skewing toward myelopoiesis (Kaufmann et al., 2018; Mitroulis et al., 2018). However, whether this expansion is autonomously driven by ST-HSCs and MPPs or is a result of upstream reprogramming of LT-HSCs remains an open question. Profiling the clonal dynamics of individual HSPC subsets after training stimuli may provide insight into which compartments are being transiently activated versus durably ‘trained’. Lineage tracing approaches, including inducible genetic barcoding systems or tamoxifen-inducible Cre drivers (Li et al., 2023), offer a promising avenue to directly test the origins of expanded progenitor subsets in response to innate immune training.

ST-HSC and MPP compartments have high proliferative capacity and fast differentiation dynamics compared to LT-HSCs, potentially making them better suited to respond to immediate immunological demands. Not only do they exhibit more pronounced transcriptional responses upon inflammatory stimulation than LT-HSCs, but they also have greater expansion capacity. It has been demonstrated that ST-HSCs and MPPs, particularly MPP3s, increase in number following BCG- (Kaufmann et al., 2018), β-glucan- (Mitroulis et al., 2018), and heme-induced (Jentho et al., 2021) trained immunity, reflecting an expansion of the myeloid-biased progenitor pool. This expansion, coupled with conserved transcriptional changes, ensures a sustained supply of functionally reprogrammed myeloid cells that have been shown to execute robust antimicrobial activity against secondary challenge with M. tb (Kaufmann et al., 2018) or display enhanced metabolic activity in response to LPS (Mitroulis et al., 2018).

A key outstanding question in the field is whether LT-HSCs act as memory reservoirs that transmit trained states downstream to shorter-lived progenitors, or if ST-HSCs and MPPs are directly reprogrammed by inflammatory signals without input from LT-HSCs. In our work, we found that transplantation of sorted LT-HSCs alone was not sufficient to confer in vivo protection in an M. avium model of trained immunity (Kain et al., 2023), suggesting that ST-HSCs and MPPs rather than LT-HSCs are responsible for innate immune memory conservation. Nevertheless, further studies are required for confirmation. In addition, the degree to which each cell compartment contributes to innate memory conservation may depend on the nature, duration, and intensity of the training stimulus.

An indirect test of the functional capacities of ST-HSC- and MPP-derived innate effector cells is to derive monocytes and macrophages from whole bone marrow preparations. Through a 7-day derivation period, whole bone marrow is cultured with granulocyte–macrophage colony-stimulating factor to generate bone-marrow-derived macrophages (BMDMs). Given that ST-HSCs and MPPs are more abundant and produce more BMDMs in such culture conditions compared to LT-HSCs, BMDM cultures provide a useful way to assess how ST-HSCs and MPPs contribute to trained immunity. It has been shown that BMDMs cultured from whole bone marrow of BCG-vaccinated mice are epigenetically imprinted to initiate a more protective response against M. tb challenge (Kaufmann et al., 2018). The initial in vivo training is dependent on IFN-γ, as epigenetic reprogramming of hematopoietic progenitors in BCG-induced trained immunity models does not occur when the IFN-γ receptor is ablated (Mitroulis et al., 2018; Kaufmann et al., 2018). Several studies have indicated that IFN-γ is required in both establishment of trained immunity and T-cell activated bacterial control (Flynn et al., 1993; Akter et al., 2022).

In contrast, maladaptive induction of innate immune memory with M. tb has been shown to impede myelopoiesis via a type I IFN-dependent process (Khan et al., 2020). Similarly, a high-fat, high-calorie Western diet (Christ et al., 2018) reprograms ST-HSCs and MPPs via IL-1β, resulting in reduced MPP abundance and expanded lymphoid-biased MPP4 populations. These alterations result in impaired host immunity with chronic low-grade inflammation (Christ et al., 2018) and a weakened ability to control infection (Khan et al., 2020).

Collectively, these findings using non-transplant models highlight that ST-HSCs and MPPs may play a significant role in innate immune memory conservation and amplification.

Mechanistically, inflammation has been shown to correlate with chromatin modifications in HSPCs that are passed on to downstream cells to amplify subsequent responses to inflammatory challenges (Netea et al., 2020; Cirovic et al., 2020). Both generation and maintenance of innate immune memory are associated with chromatin modifications such as methylation, lactylation, and acetylation of histones that alter chromatin accessibility and poise specific DNA loci for faster, higher transcriptional induction (Netea et al., 2020; Ochando et al., 2023, Ziogas et al., 2025). Many next-generation sequencing techniques, such as low-input chromatin immunoprecipitation sequencing (ChIP-seq), assay for transposase accessible chromatin (ATAC-seq), cleavage under targets and release using nuclease (CUT&RUN-seq), and cleavage under targets and tagmentation (CUT&TAG-seq), and single-cell sequencing techniques, have permitted researchers to determine the chromatin landscape in these HSPC subpopulations (Ochando et al., 2023; Figure 3).

Figure 3

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In mice, studies have shown that activating histone modifications like H3K4me3 and H3K27ac are enriched at genes associated with innate immune memory such as the metabolic regulator mTOR (Arts et al., 2016; Domínguez-Andrés et al., 2019) and pro-inflammatory cytokines IL-6 and TNF-α (Arts et al., 2016; Saeed et al., 2014). Further, sorted HSPCs (LSK+, Flt3-) have been observed to gain H3K4 mono- and tri-methylation and increased chromatin accessibility in response to LPS stimulation at genes involved in inflammatory biological processes, including innate immune response, myeloid differentiation, and anti-bacterial responses (de Laval et al., 2020). Notably, upon secondary stimulation, these LPS-trained HSPCs demonstrate a heightened excitability and a significant gain of activating histone marks H3K4me1, H3K27ac, and an overall increase in chromatin accessibility at loci associated with stem cell activation (de Laval et al., 2020). Using CUT&RUN sequencing, activating H3K27ac marks in SLAM-HSCs (Lin-, cKit+, CD48−, CD150+) have been shown to correlate with enhanced cytokine production such as the chemokine CCL5, upon M. avium infection (Le et al., 2023). Finally, metabolic processes, like oxidative phosphorylation (Sun et al., 2024) and glycolysis (Mills et al., 2024), coincide with immune training (Abhimanyu et al., 2024). These findings highlight the potential for HSCs to gain common activating histone modifications upon inflammatory stimulation, contributing to trained immunity phenotypes. However, more studies into the histone landscape of HSPCs upon inflammation are needed, as a wide range of different modifications and their mechanistic contribution to the memory phenotype remain unexplored.

Single-cell sequencing studies in human HSPCs corroborate that long-term transcriptional and epigenetic reprogramming in HSPCs can be retained in myeloid-lineage cells. For example, BCG-trained CD34⁺ human HSPCs retained transcriptional bias and chromatin accessibility toward neutrophil activation (Cirovic et al., 2020; Sun et al., 2024). While this reprogramming did not alter cell numbers or baseline function, these BCG-trained bone marrow-derived mononuclear cells showed heightened cytokine responses after being challenged with Candida albicans. Furthermore, a recent study showed that inflammation-induced reprogramming of HSCs and GMPs could be detected in human patients 6 months after recovery from SARS-CoV-2 infection, resulting in a persistent myeloid differentiation bias and hyperinflammatory state (Cheong et al., 2023). These long-lasting changes included durable alterations in chromatin accessibility at genes such as CXCR4, CCL5, and GBP5 that remained open for almost a year post-SARS-CoV-2 infection.

In addition to chromatin accessibility and histone modifications, DNA methylation has also been found to be altered in HSPCs after infection. DNA methyltransferase DNMT3A is the main cellular enzyme responsible for de novo methylation of cytosine to generate 5-methylcytosine, a mark that typically represses transcription. Interestingly, we and others showed that loci encoding transcription factors such as Batf2, Fos, and Jun, important in myeloid differentiation (Matatall et al., 2016; Liebermann et al., 1998; Taylor et al., 2024) were hypermethylated and transcriptionally repressed in Dnmt3a-mutant HSCs after infection (Hormaechea-Agulla et al., 2021). On the other hand, DNA methylation silences critical immune response genes in contexts like LPS or M. tb-induced immune tolerance (Abhimanyu et al., 2024). These findings imply that DNA methylation regulates gene transcription in the setting of infection. Despite these discoveries, the role of DNA methylation in central trained immunity remains largely unexplored.

A common set of transcription factor motifs has emerged across epigenetic studies of trained immunity. As noted above, we found that BATF2 was differentially regulated in response to infection in Dnmt3a-KO mice. Further, the loss of Batf2 (Le et al., 2023) disrupted downstream macrophage responses to pathogen challenge, highlighting its role in initiation of immune responses (Le et al., 2023). Likewise, the transcription factor CEBPβ, which is known to open chromatin and promote transcription of other TFs (AP1, IRF, and ATF) as well as innate immune response and myeloid differentiation genes such as Ifnar2, Mx2, and Itih5 (Matatall et al., 2016), has been shown to play a critical role in LPS-induced epigenetic reprogramming and central trained memory (de Laval et al., 2020). In patients with long-SARS-CoV-2, similar transcription factor programs were altered in HSPCs and monocytes, with heightened activity of TFs like JUN, NFKB1, and NFKB2, and interferon regulatory family TFs (Cheong et al., 2023). In embryonic epidermal stem cells during skin injury and repair, transcription factors including FOS and JUN act as a switch triggered by the initial training stimulus to direct stem cells’ response to different pathogens (Yang et al., 2023; Missinato et al., 2023). Altogether, these studies highlight the activation of specific TFs as a critical step in central trained immunity. This raises the possibility that transcription factors act as pioneer factors which open chromatin to enable the acquisition of DNA methylation and histone modifications. Whether chromatin marks or transcription factors are the key initiating event for central trained immunity remains an active area of research in the field (Netea et al., 2020; Ochando et al., 2023).

Altogether, histone modifications and chromatin openness at key transcription factor binding motifs have been shown to be conserved in HSCs and downstream effector myeloid cells after immune training, suggesting that conserved chromatin accessibility changes may provide the mechanism for enhanced innate immune responses in central trained immunity. However, the mechanisms by which such marks are passed down through ontogeny remain undefined. Are transcription factors stable enough to remain associated with chromatin through cell division and thereby facilitate histone modifications? Or are these histone modifications conserved through cell divisions that occur during differentiation? These challenging questions will serve as guideposts for future research.

While a variety of stimulants produce trained immunity phenotypes, a common set of inflammatory cytokines plays key mechanistic roles downstream of these stimulants. Cytokines including IL-6 (Cheong et al., 2023), IFNs (Kaufmann et al., 2018; Khan et al., 2020), and IL-1 (Moorlag et al., 2020) are commonly reported inducers of innate memory in models of trained immunity. These cytokines, particularly IL-6 and IL-1, can be produced both by HSPCs themselves (Granick et al., 2012), their progeny, as well as immune and niche cells in the bone marrow microenvironment which therefore contribute significantly to trained immunity induction (Mitroulis et al., 2020). We demonstrated that IFNγ is essential for trained immunity, as the loss of the IFNγ receptor resulted in the abrogation of trained immunity protection (Kaufmann et al., 2018). IL-1 and type I IFN are crucial for β-glucan-mediated trained immunity (Kalafati et al., 2020; Mitroulis et al., 2018; Moorlag et al., 2020; Gow et al., 2007), leading to proliferation and differential skewing of hematopoietic progenitor cells. Specifically, GMPs, Gr1⁺CD11b⁺ cells, and myeloid cells proliferate and serve in a protective role, such as in neutrophil-mediated anti-cancer responses (Kalafati et al., 2020; Geller et al., 2022) and macrophage-mediated responses to control M. tb (Moorlag et al., 2020). Moorlag et al. demonstrated that reprogramming of HSPCs relied on IL-1, as inhibition of IL-1 signaling impaired the effects of β-glucan-mediated trained immunity (Moorlag et al., 2020).

These studies highlight the necessity of inflammatory cytokines for the generation of central trained immunity. Notably, inflammatory cytokines like IL-6 are elevated in aging and promote myeloid-biased differentiation and hyperinflammatory innate immune cells, a concept known as inflammaging (Chung et al., 2006). Considering the similarities between inflammaging and trained immunity, the question of whether cytokines alone can confer trained immunity is a field of active investigation. We showed that a single dose of recombinant IFNγ reprograms HSPCs leading to higher metabolism and more robust and efficient immune responses in the downstream macrophages (Kain et al., 2023). This phenotype persisted even after HSPC transplant. The question remaining is whether a strong enough cytokine signal, or combination of cytokines, is indeed sufficient to generate central trained immunity, or whether stimuli recognition itself has shaping potential for the epigenetic reprogramming and downstream immune response. Upcoming studies are geared to clarify whether ‘clean’ training stimulants, such as pure cytokine cocktails, are sufficient to promote central training and host immunity.

Notably, studies indicate that HSPCs do not all respond to inflammatory cytokine stimulation alike, opening the possibility that specific subpopulations get differentially programmed with every inflammatory insult. HSCs express receptors for inflammatory cytokines and pathogen-associated molecular patterns that shape HSC cellular and transcriptional outputs. Both human and murine HSPCs express many pathogen recognition receptors such as TLR-1, TLR2, TLR3, TLR4, TLR6, TLR7, TLR8, NOD, RigI-like receptors, and STING/GAS that can directly interact with stimuli, activate downstream signaling pathways, and promote HSC loss of quiescence (King and Goodell, 2011; Baldridge et al., 2010). For instance, HSCs process LPS through interactions with TLR4, recruiting C/EBPβ to result in a transient increase of LT-HSCs, MPP2, MPP3, and GMP numbers and stable changes in chromatin accessibility of Flt3⁻LSK cells (de Laval et al., 2020). Single-cell studies indicate that HSPCs differentially process inflammatory signals to initiate the reprogramming that produces and maintains central trained immunity, leading to heterogeneity in responses (Kain et al., 2023).

Despite the recognition that HSPCs are highly heterogeneous, it remains unknown if all HSPCs have equal capacity for innate immune memory. Initial studies of BCG-vaccinated humans found that not all patients developed trained immune memory (Verma et al., 2017). Taking peripheral monocytes from healthy volunteers pre and post BCG vaccination, Verma et al. described varying levels of cytokine production in response to in vitro stimulation, thus categorizing subjects into ‘responders’ and ‘non-responders’. BCG responsive changes were attributed to DNA hypomethylation at regions such as ADCY3, leading to immune activation. The researchers did not study histone modifications in this study, but others have recently found increased chromatin accessibility in HSPCs of BCG-vaccinated individuals (Sun et al., 2024). This variability in response raises questions about the universality of trained immunity as an immunization strategy and highlights that genetic factors or environmental conditions may contribute to trained immunity in yet unknown ways.

Responder and non-responder variability has also been observed on a cellular level in HSPC single-cell transcriptomic studies in various inflammation models, including BCG vaccination (Kaufmann et al., 2018), LPS stimulation (de Laval et al., 2020), and M. avium infection (Kain et al., 2023). In some cases, distinct transcriptional states within HSPCs could be clustered in alignment with fate determination. Specifically, single-cell RNA sequencing on bone marrow HSPCs revealed multiple clusters of MPP3s, with one cluster containing a transcriptional signature indicative of granulocytic bias (Kaufmann et al., 2022). Similarly, a single-cell RNA sequencing study of HSPCs in the setting of M. avium infection revealed heterogenous transcriptional responses, with a minority of cells driving the significant upregulation of inflammatory genes (Kain et al., 2023). Altogether, these single-cell studies indicate that HSPC populations do not respond as a monolith to inflammatory stimuli; rather, there is significant heterogeneity even within cell types to produce appropriate inflammatory responses. Thus, trained immunity phenotypes may be driven by a small subset of total HSPCs. It is tempting to speculate that heterogeneous reprogramming is an adaptive feature, allowing non-responsive HSPCs to continue basal functions or be poised for future training by alternative agents. Alternatively, heterogeneity may be due to spatial variation in infection and inflammatory cytokine density and spatial distribution of the HSPCs in the bone marrow. Spatial transcriptomics methods (Crosse et al., 2020) could shed light on whether ‘responder’ cells are clustered relative to hubs of infection or mature responder cells producing cytokines in the bone marrow.

With the expansion of single-cell sequencing, a growing body of literature suggests heterogeneity even within the canonically defined HSC compartment (LSK, CD150-negative, CD48-positive) at baseline and upon inflammatory activation. For instance, myeloid-biased CD41-positive HSCs (Gekas and Graf, 2013) are a potential driver of central trained immunity (Mitroulis et al., 2018; Kain et al., 2023; de Laval et al., 2020). We recently described an infection-activated HSC subset (IA-HSC) stimulated by M. avium that expresses both LSK and activation markers, such as CD81, CD24a, and CD9 (Kain et al., 2023). Notably, the IA-HSCs can be sorted and transplanted in murine models, thus providing the potential to investigate whether these cells are the source of trained immunity. Similar subsets of ‘inflammatory memory’ HSCs have been identified in human studies (Zeng et al., 2023). Future studies aim at parsing out how the heterogeneity in HSCs relates to trained immunity phenotypes, while deeper epigenetic sequencing methodologies (Figure 3) will enable further definition of HSC subpopulations both in health and disease in humans (Zeng et al., 2023).

Preferential expansion of a specific HSPC subset is reminiscent of clonal hematopoiesis of indeterminate potential (CHIP), a preleukemic condition in which the bone marrow of older individuals harbors an expanding population of cell clones with somatic mutations, often in cancer-driver genes (Jaiswal and Ebert, 2019). Like trained immunity, CHIP clones can respond to environmental stressors like inflammation and significantly expand their progeny, ultimately gaining a cellular advantage in the bone marrow and peripheral blood (Cao et al., 2024; Florez et al., 2022; Avagyan and Zon, 2023). Inflammation-mediated expansion, epigenetic changes, and cancer predisposition are fundamental themes shared between the fields of central trained immunity and CHIP (Chavakis et al., 2022). As such, it is worthwhile to consider whether responder cells poised for trained immunity exist within hosts in the same way that rare somatic mutations arise, and whether inflammatory training may lead to their expansion and selective advantage like in CHIP clones. Indeed, if innate immune memory is actually achieved by selection and expansion of preexisting populations, perhaps central trained immunity is really a manifestation of clonal selection rather than training and immunological memory.

In sum, recent studies provide strong evidence that HSPCs can cell autonomously sustain trained immunity phenotypes in both mice and humans, supporting long-term production of innate memory effector cells with enhanced immune function. The mechanisms by which HSPCs support central trained immunity are fascinating. Here, we have described two major and non-mutually exclusive mechanisms: (1) inflammatory stimuli select and alter lineage fate determination of HSPC progeny, reshaping immune cell populations; (2) reprogramming of HSPCs generates downstream progeny that are transcriptionally and metabolically poised for enhanced immune function. Indeed, both mechanisms seem to occur in parallel. While the field of central trained immunity continues to expand, many unknowns remain. The following questions remain critical priorities to translate central trained immunity for therapeutic benefit.

First, epigenetic mechanisms by which HSPCs maintain central trained immunity remain poorly understood. Transplant studies indicate that HSPCs sustain changes that last for months or years and can be passed to progeny cells, implying an epigenetic change. While histone modifications and DNA methylation are considered the mediators of reprogramming signatures, the causal relationship between chromatin marks and trained immunity has not been defined through loss of function studies. Likewise, the association of specific epigenetic marks with defined training results is still pending. Most studies have focused on H3K4me3 and H3K27ac, but these are typically transient marks; a number of other marks may be better candidates for memory functions. Loss and gain of function studies will indisputably demonstrate a role for a particular chromatin modification, gene locus, or transcription factor in trained immunity, which can ultimately also be therapeutically targeted for enhancement or clearance.

Second, alternative mechanisms for HSC memory induction such as sustained changes in mitochondria need to be considered (Bonora et al., 2024; Hinge et al., 2020). Just as epigenetic reprogramming is critical for trained immunity, it is well documented that metabolic rewiring, particularly at the mitochondrial level, is critical for innate immune memory (Netea et al., 2020; Arts et al., 2016; Abhimanyu et al., 2024). Notably, the methyl groups and acetyl-CoA that serve as key substrates for epigenetic modifications are products of mitochondrial metabolism (Netea et al., 2020; Ferreira et al., 2024; Riksen and Netea, 2021; Wu et al., 2023). Considering that alterations in critical metabolic pathways such as oxidative phosphorylation in HSPCs are consistently observed in trained immunity models (Mills et al., 2024; Sun et al., 2024; Abhimanyu et al., 2024), metabolic rewiring may in fact be the driver of epigenetic alterations.

Third, as described throughout this review, hematopoietic cells at different stages of differentiation, from HSCs to lineage-committed progenitors, contribute to central trained immunity. The HSPC subcompartment most critical for trained immunity remains unknown, and the major responders and mediators may be context dependent. Current research relies on transplantation of mixed HSPC populations that are limited by the low number of primitive cells and short lifespan of downstream progeny. It is worth acknowledging that murine transplant studies do not rule out the possibility that trained immunity may be transmitted by non-cell autonomous mechanisms (e.g. alterations of the niche). However, they do provide strong rationale for pursuing further mechanistic studies of cell autonomous central trained immunity, with potential benefits for HSC transplant recipients. In the future, in vivo barcoding and mosaic models will enhance these studies. Single-cell and spatial multiomic studies will ultimately address how many reprogrammed HSPCs are necessary to generate functionally relevant degrees of immune protection. Furthermore, these studies will elucidate whether innate memory protection induced by one specific stimulus diminishes trained immunity potential for other stimuli. Finally, detailed studies of changes in the bone marrow niche after inflammatory challenge will shed light on non-cell autonomous mechanisms for central trained immunity.

Enhanced immunity conferred by innate immune training has exciting translational potential. Providing nonspecific enhanced immunity would be of critical value in the setting of novel pandemics for which antigen-specific vaccines are not yet available. Further, immune training of HSPCs could improve outcomes for recipients of bone marrow transplants, for whom infection remains a leading cause of death. However, wide heterogeneity in HSPC transcriptional responses and epigenetic marks in trained immunity studies, in both murine and human trials, remains a major limiting factor for translation of trained immunity. Studies such as those published by Verma et al. show that current approaches to induce trained immunity may not be successful for everyone, even with a healthy background (Verma et al., 2017). Furthermore, the variable memory observed in long-COVID patients indicates that trained immunity responses may be maladaptive for some individuals (Cheong et al., 2023). Thus, many more studies to explicate the cellular and molecular basis of trained immunity are needed to actualize these goals.

In summary, it is an exciting time for research into central trained immunity. Inflammatory training of HSPCs confers long-term enhanced immunity against secondary infectious challenges with measurable changes in prevalence and function of progenitors and innate immune cells. Current studies indicate that immunological training throughout life may shape the evolution of the stem and progenitor cell compartment, yielding manifold layers of immune memory. This phenomenon has been described in human epidemiologic and single-cell functional studies and is reproducible in mouse models, with clear implications for human health. While the crucial role of HSPCs in maintenance of memory function in innate immune cells has been revealed, the field is now poised to address the detailed mechanistic basis for this phenomenon. Future clinical research envisions the development of methodologies to train donor HSPCs prior to transplant, resulting in reduced infectious complications after transplant. Alternatively, elucidation of cellular sources of trained immunity may lead to strategies to select for these cells as an immunologically enhanced donor pool. Finally, elucidating the epigenetic bases for trained immunity may lead to bioengineering approaches that recreate these effects in patients without the need for immune training. Such approaches can be utilized in the clinic to offset immune dysfunction in aging, to enhance tumor immunotherapy, or to curb the dangerous effects of autoimmunity.

Table 1 describes the different subpopulations of HSPCs that have been shown to conserve trained immunity signatures. Depending on the HSPC population, trained immunity has still been observed at specific selected experimental endpoints spanning from a few weeks to years post-training. Reversal or loss of training signatures has yet to be demonstrated.

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Author details

1. Brandon T Tran

   1. Department of Pediatrics, Division of Infectious Diseases, and Stem Cells and Regenerative Medicine Center, Baylor College of Medicine and Texas Children’s Hospital, Houston, United States
   2. Program in Cancer and Cell Biology, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, United States

   Contribution

   Visualization, Writing – original draft

   Contributed equally with

   Vidthiya Jeyanathan and Ruoqiong Cao

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9800-8953

2. Vidthiya Jeyanathan

   Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada

   Contribution

   Visualization, Writing – original draft

   Contributed equally with

   Brandon T Tran and Ruoqiong Cao

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0009-0006-7527-7137

3. Ruoqiong Cao

   1. Department of Pediatrics, Division of Infectious Diseases, and Stem Cells and Regenerative Medicine Center, Baylor College of Medicine and Texas Children’s Hospital, Houston, United States
   2. Program in Immunology and Microbiology, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, United States

   Contribution

   Visualization, Writing – original draft

   Contributed equally with

   Brandon T Tran and Vidthiya Jeyanathan

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-8100-2136

4. Eva Kaufmann

   Department of Biomedical and Molecular Sciences, Queen’s University, Kingston, Canada

   Contribution

   Supervision, Funding acquisition, Project administration, Writing – review and editing

   For correspondence

   eva.kaufmann@queensu.ca

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-7965-9200

5. Katherine Y King

   1. Department of Pediatrics, Division of Infectious Diseases, and Stem Cells and Regenerative Medicine Center, Baylor College of Medicine and Texas Children’s Hospital, Houston, United States
   2. Program in Immunology and Microbiology, Graduate School of Biomedical Sciences, Baylor College of Medicine, Houston, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Project administration, Writing – review and editing

   For correspondence

   kyk@bcm.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5093-6005

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