Prenatal training grounds: the developmental origins of chronic immune disease

Abstract

Background

Immune cells seed tissues in orchestrated waves beginning in utero. While the impact of prenatal environmental exposures is well-documented in neuroimmunology, the influence of maternal-fetal interactions on systemic immune development and its contribution to lifelong chronic inflammatory disease remains underappreciated.

Main body

This narrative review synthesizes recent ontogeny data to demonstrate how diverse prenatal cues, ranging from maternal infection to microbial-derived metabolites, function as a “prenatal training ground” for the developing fetal immune system. These maternal signals interact with specific waves of hematopoiesis to shape long-lived tissue-resident immune cells. In many tissues, these prenatally programmed populations persist into adulthood, acting as lifelong immunological rheostats that dictate the type and intensity of local inflammatory responses. Furthermore, we critically evaluate the translational gaps in the field, highlighting fundamental species-specific differences in developmental timelines that necessitate careful alignment between preclinical animal models and human biology.

Conclusions

We propose that many chronic immune conditions are not strictly adult-onset in their etiology, but rather adult-manifesting, making prenatal immune seeding a critical, yet overlooked, determinant of long-term health. Current interventions largely focus postnatally, but reorienting research and clinical focus toward prenatal factors provides new insights into the developmental origins of chronic inflammation and offers a novel therapeutic window to optimize the health trajectory of the next generation.

Highlights

Maternal cytokines, diet and microbial-derived metabolites shape fetal immune development.

Fetal-origin immune cells persist in adult tissues, exhibiting distinct functional responsiveness.

These prenatally programmed tissue-resident cells influence local inflammation.

Translating preclinical maternal-fetal findings requires critical alignment with human immune ontogeny.

Longitudinal birth cohorts are required to characterize the fetal exposome and its consequences on lifelong immune function.

Introduction

During gestation, the fetus undergoes rapid and intricate developmental processes critical for the formation of healthy organs and tissues. This development is governed heavily by maternal health and nutrition. To meet increasing physiological demands, expectant mothers are routinely prescribed prenatal vitamins and supplements to support optimal fetal growth [1]. Decades of research has shown how deficiencies in maternal nutrition are linked to congenital abnormalities. For instance, inadequate folate intake is a well-documented cause of neural tube defects such as spina bifida and the introduction of routine folic acid supplementation significantly reduces these risks [2]. While the visible consequences of folate deficiency such as congenital malformations have underscored the importance of maternal diet, the role of maternal health in shaping the functional development of less overt systems, including the immune response, remains less understood.

The immune system, while less visible, is vital for lifelong health and protection. Its development begins with yolk sac hematopoiesis in utero and is guided by complex microenvironmental cues [3]. Traditionally, the postnatal period, when a neonate’s body is first colonized by microbes, has been considered the primary driver of immune education and maturation [4]. However, emerging research challenges this notion, suggesting that maternal factors during pregnancy play a critical role in shaping offspring immunity both before and after birth [5, 6]. Molecules exchanged between maternal and fetal circulation including cytokines and metabolites can influence fetal hematopoiesis and immune programming. Accordingly, improving our understanding of the factors that guide fetal immune development is essential as the clinical implications of prenatal health extend well beyond life in the womb.

The Developmental Origins of Health and Disease (DOHaD) theory suggests that disrupted early-life exposures can impact fetal and neonatal development and increase the long-term risk of adult-onset diseases. Several reviews have highlighted skewed development of hematopoietic stem and progenitor cells in perinatal life as a contributing factor to lifelong health and disease [7]. In this narrative review, we synthesize recent ontogeny data with clinical disease risk to suggest that prenatal maternal exposures also skew tissue-resident, long-lived immune cells, contributing to tissue-specific allergic and autoimmune disease susceptibility. We share current insights into how maternal health and nutrition shape fetal immune development through the provision of key nutrients and the placental passage of inflammatory mediators. While research into in utero programming of immunity has made significant strides, much of our mechanistic understanding currently relies on animal models. Therefore, we comment on the inherent heterogeneity of this evidence and the translational gaps that remain, and highlight outstanding questions in the field that warrant further investigation.

An overview of murine and human fetal immune development

The immune system begins to develop in utero via distinct and stereotypically-timed waves [8] beginning with the production of blood and immune cell precursors in the extraembryonic yolk sac at around 2–3 weeks post-conception in humans. The yolk sac has been reported to be the source of the first primitive erythroid cells, macrophages, and possibly other innate hematopoietic cell lineages from progenitor-like cells, though timed analyses to exclude detection of cells from other sources in the circulation is a challenge [9]. At around 4 weeks post-conception, embryonic hematopoietic progenitor activity begins to develop independently in the aorta gonad mesonephros (AGM) region of intra-embryonic mesoderm. Yolk sac and AGM derived progenitor cells then seed the fetal liver, which becomes the major site of hematopoiesis until the second trimester of development. In humans, fetal bone marrow is colonized around 11 weeks post-conception, but then rapidly becomes the dominant organ of hematopoiesis after 20 post-conception weeks of development (Fig. 1).

Fig. 1.

Ontogeny of murine and human fetal immune cell development. (A) Timeline of hematopoietic sites in the mouse, highlighting sequential contribution of yolk sac, aorta-gonad-mesonephros (AGM), fetal liver and bone marrow to immune cell production across gestation and early postnatal (PN) life, with bone marrow hematopoiesis initiating late in gestation and functionally maturing during the first 1–2 postnatal weeks. (B) Timeline of hematopoietic sites in the human fetus, showing transition from yolk sac and AGM to fetal liver and then to bone marrow, which becomes the major hemopoietic organ by the mid-second trimester and contributes to support hematopoiesis through late gestation and infancy. The horizontal brown bars denote birth in both species, emphasizing the relatively greater postnatal establishment of bone marrow-driven immunity in mice compared with its extended in utero maturation in humans

Yolk sac, AGM, fetal liver, and bone marrow derived immune cells seed peripheral tissues including the developing brain, lungs, skin, and gut to establish long-term tissue-resident immunity. Some of these immune cells, such as tissue-resident macrophages [10] and subsets of innate lymphoid cells (ILC) [11], establish lifelong self-maintained populations that persist largely independent of replenishment by bone marrow derived precursors, while others are gradually replaced by circulating immune cells. Accordingly, the adult immune system contains a mosaic of cells emerging at various times during ontogeny, also termed layered hematopoiesis.

The fetal hematopoietic stem and progenitor cell (HSPC) compartment can directly perceive maternal infection or inflammation through the transplacental passage of cytokines and pathogen-associated molecular patterns (PAMPs), leading to training or biased cell output [7]. Such trained immunity at the stem cell level, characterized by persistent epigenetic and metabolic reprogramming, may leave a lasting imprint on adult immune output by altering the composition and functionality of the lifelong hematopoietic stem cell (HSC) pool. Beyond stem and progenitor cells, the developmental origins of mature immune cells in tissues also have significant relevance for their function. Both mouse and human studies have demonstrated that early waves of immune cells often possess functional properties distinct from their adult-derived counterparts. Evidence from mouse models has identified “early-life-origin” B cells, including B1a cells and IgA plasma cells, that arise during a restricted neonatal window and contribute substantially to the adult B cell pool [12]. These early-life B cells have unique specificities, such as memory clonotypes against rotavirus, that are not recruited if the same antigens are first encountered in adulthood. Similarly, the developmental origins of CD8 T cells dictate their fate and function during infection. Fetal-derived CD8 T cells possess an effector-like chromatin landscape that poises them for rapid, innate-like effector responses, while adult-derived CD8 T cells preferentially differentiate into long-lived memory precursors [13]. This functional stratification is mirrored in humans, where a fetal wave of human type 3 effector γδ T cells with restricted TCR diversity develops in the embryonic period and persists into adulthood [14]. As such, maternal signals can influence tissue-resident immunity by modifying local niches or providing gestational cues that program long-lived, mature lineages independently of the bone marrow pool. The clinical implications of these altered gestational cues on subsequent clinical disease risk are addressed in the following sections.

While the fundamental waves of layered hematopoiesis are evolutionarily conserved, the temporal execution of these programs varies significantly between species. Murine systems are widely used to model human immune development due to their accessibility, short lifespan, easy maintenance and a panoply of genetic tools that can be used for fate mapping and functional manipulation. Mice provide invaluable insights into immune system development, disease mechanisms, and are a resource for testing therapeutic interventions. Those distinct advantages aside, it is important to recognize that differences exist between the development of human versus mouse immunity [15]. For example, as we and others have shown, CD34 regulation differs between human and mouse mast cells. In humans, CD34 expression is lost upon mast-cell differentiation, while mature murine mast cells retain CD34 expression [16]. As CD34 is important for blocking adhesion and facilitating homing of mast cells in mice [17], this may imply that mast cells populate tissues differently in humans. Interspecies differences also extend to immune development in utero, and understanding these differences is essential for accurately interpreting and translating findings from murine models to human biology. Notably, by the end of gestation, a mouse fetus has all major organs formed but remains at a relatively early stage of maturation, roughly equivalent to that of an early second-trimester human fetus. As a result, organ maturation occurs postnatally in mice which is an important consideration when studying immune development.

Many of the developmental processes that are completed in utero by the second and third trimester in humans occur after birth in mice and are influenced heavily by postnatal environmental exposures (Tables 1 and 2). That important caveat aside, while mouse gestation is shorter and offspring are born immunologically immature compared to humans (Fig. 1), findings from murine models are still relevant. If maternal exposures during gestation can impact fetal immune development in mice, it is reasonable to infer that similar exposures during the more extended and immunologically advanced gestational period in humans could also shape offspring immunity. Much of our mechanistic understanding of fetal programming relies on mouse models. To accurately translate findings from the bench to the clinic, it is necessary to align these developmental milestones. Table 3 summarizes key divergent features, highlighting how the timing of events such as thymic development, bone marrow functionalization and maternal antibody transfer creates distinct windows of vulnerability or opportunity for immune imprinting that requires consideration of species-specific differences and warrant careful validation in human studies. With this comparative framework established, we can better evaluate how the “prenatal training ground” is influenced by external cues. Whether through acute pathogen exposure or chronic nutritional shifts, the following sections detail how maternal signals intercept these stereotypical waves of development to permanently alter the offspring’s immune landscape.

Table 1.

Prenatal emergence of human immune cell populations

HUMAN
Cell type		Timeline	Description	Citation
Hematopoietic stem and progenitor cells	Primitive	2.5 weeks	Yolk sac	[9, 18–21]
	Transient Definitive	4–6 weeks	AGM
	Definitive	6–10 weeks	Fetal liver
	Definitive (predominantly granulopoiesis at this early stage)	10–15 weeks	Fetal bone marrow
Erythrocytes	Primitive	2–3 weeks	Yolk sac	[22]
Mast cells	Precursor	4 weeks	Yolk sac	[9, 23]
	Mature	5 weeks	Yolk sac
	Mature	6–7 weeks	Peripheral tissues
NK cells	Precursors (lymphoid-biased progenitor)	4–5 weeks	Yolk sac and AGM	[9, 24–26]
	Mature	6 weeks	Fetal liver
	Mature	8–9 weeks	Fetal intestine
	Mature	15 weeks	Fetal spleen
ILCs	Precursors (lymphoid-biased progenitor)	4 weeks	Yolk sac	[9, 26, 27]
	Precursors (lymphoid-biased progenitor)	5 weeks	AGM
	Precursors (lymphoid-biased progenitors; RORC and KIT expressing pre-ILCs)	5 weeks	Fetal liver
	Mature ILC3	12 weeks	Fetal intestine and lungs, amniotic fluid
	LTi cells (Lin− CD45int CD127hi)	13–22 weeks	Fetal mLN, pLN and spleen
Eosinophils	Precursors	5 weeks	Fetal liver	[28]
Neutrophils	Precursors	5 weeks	Fetal liver	[28]
	Mature	10–13 weeks	Fetal bone marrow
Macrophages	CD14+ monocytes/ macrophages	12–22 weeks	Peripheral tissues (spleen, skin, thymus, lung)	[29, 23]
Dendritic cells	Precursor	4–5 weeks	Yolk sac	[9, 29]
	Conventional DCs	5 weeks	Fetal liver
	pDCs, cDC1, and cDC2	12–22 weeks	Peripheral tissues (spleen, skin, thymus, lung)
B cells	Precursors (CD10− PreProB- and CD10+ ProB-progenitors)	7–8 weeks (precursors)	Fetal liver	[30–33]
	Precursors (CD10− PreProB- and CD10+ ProB-progenitors)	11 weeks	Fetal bone marrow
	Mature (B1 and B2 B cells)	8–9 weeks	Fetal liver, fetal intestine
T cells	Lymphoid progenitors (IL7R+)	5 weeks	AGM, Fetal liver	[22, 34–37]
	Precursors	7–8 weeks	Thymus
	In circulation	10–14 weeks	Blood
	Precursors	7–8 weeks	Thymus
	In circulation	10–14 weeks	Blood

Timeline and anatomical sites for hematopoietic progenitors and major innate and adaptive immune cells, with bolded entries indicating the cell types depicted in Fig. 1

Table 2.

Prenatal emergence of murine immune cell populations

MOUSE
Cell type		Timeline	Description	Citation
Hematopoietic stem and progenitor cells	Primitive	E7.0-9.0	Yolk sac	[19, 38–43]
	Pro-definitive/ Definitive	E8-10.5	AGM
	Definitive	E10.5-11.5	Fetal liver (seeded by YS-derived EMPs and AGM-derived HSCs)
	Definitive	E16.5-18	Bone marrow
	Embryonic MPPs	E10.5	AGM/ umbilical and vitelline arteries
Erythrocytes	Primitive	E7.0-9.0	Yolk sac	[44]
	Definitive	E8.25	Yolk sac
	Definitive	E10.5	Fetal liver
Mast cells	Precursors	E9.5-13	Yolk sac	[45–49]
	Precursors	E13-15	Fetal liver
	Mature	E16	Skin
	Mature	PN 4 weeks	Glandular stomach
	Mature	PN 6 weeks	Peritoneal cavity
NK cells	Precursors	E13.5-17.5	Fetal liver	[50, 51]
	Immature NK cells	E14.5-E15.5	Fetal liver, spleen and thymus
	Cytotoxic NK cells	E16.5-18.5	Fetal liver and spleen
ILCs	Common lymphoid progenitors (IL-7Rα+ Sca-1low c-Kitlow)	E12.5-14.5	Fetal liver	[52]
	CHILPs (Lin− Id2+ IL7Ra+ CD25− α4β7+)	E15.5	Fetal liver	[53]
	ILC precursors (Lin−IL-7Rα+ c-Kit+ α4β7hi PLZFhi)	E14	Fetal liver	[54]
	LTi progenitors (embryonic)	E8.5-10.5	AGM (in adult, embryonic LTi replaced by HSC-derived cells)	[55]
	LTi-like cells (CD4+ CD3− α4β7+)	E12.5–E17.5 PN0	Fetal liver, spleen, lymph nodes	[56–58]
	ILC2	E17.5	Fetal lung, small intestine and skin	[11]
Eosinophils	Precursors	E13.5-16.5	Fetal liver	[59]
Neutrophils	EMP-derived	E11.5-14.5	Fetal liver / circulation	[40, 60]
	HSC-derived	E14.5-18.5	Fetal liver
Macrophages	Precursors	E7.5-9.5	Yolk sac	[61–63, 10, 64]
	Csf1r+ EMPs and CX3CR1+ pre-macrophages	E8.5-E12.5	Yolk sac and fetal liver
	Langerhans cell precursors	E18	Skin
	Langerhans cells	PN2-PN7	Skin
Dendritic cells	CD11c+ DCs and plasmacytoid pre-DCs	E17	Thymus	[65]
	CD8α+ DCs	PN7	Thymus
	CD4− CD8α− CD205+ DCs	PN1-27	Spleen
B cells	Precursors	E11-12	AGM	[66–68]
	Pro-B cells (preferentially differentiate into B1 cells)	E11-E16	Fetal liver
	B1 B cell progenitor	E15-E18	Fetal bone marrow
T cells	Precursors	E10-E14	Thymus	[56, 69–71]
	Intraepithelial lymphocytes (IELs)	E14-E17; E16-E18; E18-PN	DETC; Reproductive tract; Small intestine
	Mature (CD4+and CD8+)	PN3	Spleen and LN

Timeline and anatomical sites for hematopoietic progenitors and major innate and adaptive immune cells, with bolded entries indicating the cell types depicted in Fig. 1

Table 3.

Species-specific differences in immune ontogeny and its translational implications

Feature	Human development	Murine development	Clinical / Translational Implications
Thymic and T cell development	Thymic development starts at ~ 8–9 weeks, largely complete in utero. Tregs develop early in fetal life and can be found in periphery before birth.	Thymic development begins in late gestation, Treg generation occurs during a restricted postnatal window	Prenatal exposures in human impact a more mature T cell compartment. In humans, tolerance promoting interventions likely have a greater impact in utero than in the neonatal period
Shift to bone marrow hematopoiesis	Dominant by second trimester (~ 20 weeks)	Occurs very late in gestation, matures functionally 1–2 weeks post-birth	Earlier human BM functionalization allows the lifelong HSC pool to establish its niche in utero. This may permit cumulative epigenetic imprinting by homeostatic maternal factors in human rather than the acute postnatal stress factors that dominate in mouse models
Dendritic cell maturation	Functional subsets (pDCs, cDCs) in lungs by 12–22 weeks gestation	Most DC development occurs in late embryonic or early postnatal life	Human fetal tissues contain active antigen-presenting cells capable of sensing maternal/ environmental signals significantly earlier than murine counterparts
IgG transfer	Significant transplacental transfer during 2nd and 3rd trimesters	Minimal transplacental transfer, mostly through colostrum postnatally	The human fetal immune system is heavily buffered by maternal antibodies in utero, which may modulate the initial “training” of fetal immune cells by environmental antigens
Gestational duration and exposures	Long (~ 40 weeks), allows for chronic, cumulative exposure to maternal factors (i.e. diet, pollutants, etc.).	Short (~ 20 days), the impact of acute or transient exposures may be exaggerated since they influence a much larger percentage of the total developmental window	Extended gestational period in humans suggests that low-grade, chronic exposures as opposed to acute exposures may have more clinical relevance than mouse models suggest
Placental architecture	Hemomonochorial – a single syncytiotrophoblast layer separating maternal blood from fetal capillaries	Hemotrichorial – three trophoblast layers (two syncytial, one mononuclear) forming the interhemal barrier	The layered murine barrier provides higher degree of physical resistance to vertically transferred molecules. Human placental transfer is likely vastly different. For example, transplacental transmission of cytomegalovirus in humans is generally not observed in immunocompetent mice.

This table highlights select examples of fundamental developmental differences between humans and mice. Key milestones, such as the timing of definitive hematopoiesis and immune cell maturation, occur largely prenatally in humans but postnatally in mice. Aligning these divergent timelines is critical for accurately translating preclinical windows of vulnerability into human preventative health strategies

Priming of fetal immunity in utero

The stereotypical waves of fetal immune development are continuously modulated by a complex dialogue with the maternal environment. In health, this interaction is mediated by the placenta, a highly vascularized and selective tissue enabling the maternal-fetal exchange of nutrients and gases sustaining fetal development. Beyond its function for basic physiological support, the placenta controls the fetal exposure landscape yet remains one of the most understudied organs in human physiology. Characterizing the factors influencing placental selectively and how it actively facilitates or restricts specific maternal signals is a significant undertaking that lies outside the scope of this review. Instead, we focus on the functional consequences of the vertically transferred cues, including the specific infections, pathogen-derived antigens, maternal cytokines and metabolites that have been demonstrated to cross the placental interface. By examining these cues, we can begin to decode how the maternal environment programs fetal immune development and function with enduring effects that persist well into postnatal life.

Infections

Maternal infection during pregnancy can negatively impact fetal development, particularly infections caused by TORCH pathogens (i.e. Toxoplasmosis, Other [often syphilis/parvovirus] Rubella, Cytomegalovirus and Herpes Simplex Virus / Hepatitis B Virus) that can breach the placental barrier to directly infect the fetus. Historical birth cohort studies of mother-child dyads provide some of the first insights into this phenomenon in a population-level context. In the mid-1900s, positive delayed-type hypersensitivity skin tests were documented in children born to mumps-virus infected mothers, suggesting that prenatal infections can prime antigen-specific T cells in utero [72]. More recent clinical studies of placental malaria infection show that fetal exposure to malarial antigens early in gestation can induce tolerance and impair the offspring’s ability to mount anti-malarial immune responses later in life [29], while others demonstrate the priming of highly specific, protective T cells that persist postnatally ([73], reviewed by Feeney M.). The extent to which in utero antigen exposure drives tolerogenic versus protective immune responses likely depends on the timing of infection during gestation (further discussed below in “Gestational timing of prenatal exposures”).

Mechanistically, this temporal dichotomy in immune fate (induction of tolerance early in gestation versus effector priming later) may be linked to layered hematopoiesis and changing demands during pregnancy. During the first and early second trimesters, hematopoiesis is predominantly driven by the fetal liver (Fig. 1). T cells derived from these early fetal liver progenitors are epigenetically distinct from adult T cells and possess a higher intrinsic propensity to differentiate into FOXP3⁺ regulatory T cells (Tregs), essential to prevent potentially fatal alloimmune reactions against maternal antigens in utero [74, 75]. Fetal antigen-presenting cells during this early window are also functionally distinct, expressing lower levels of co-stimulatory molecules and favoring induction of tolerance [29]. However, as gestation progresses, definitive hematopoiesis shifts to the bone marrow and introduces a new wave of immune cells with “adult-like” effector functions in parallel with gradual maturation of the fetal antigen-presenting cell (APC) compartment [74, 76]. Consequently, late-gestation exposures encounter an immune system equipped for the generation of functional, protective effector-memory T cells [73, 77].

Preclinical murine models show that, beyond direct infection, the developing fetus may also be sensitized by pathogen-derived antigens. In mice, offspring born to mothers exposed subcutaneously to Mycobacterium tuberculosis antigen Ag85A during the second week of gestation exhibited better control of infection postnatally, driven by the priming of the fetal immune system by transplacental antigen transfer [78]. These findings underscore that the immune system of the developing fetus is responsive to environmental inputs and prenatal immune sensitization is not uniformly suppressive. Characterizing the fetal immune response to diverse in utero antigenic exposures and timing is essential to understanding how these exposures shape immunity throughout the lifespan.

Maternal immune activation

In the absence of vertical transmission (direct pathogen exposure), maternal immune activation (MIA) during pregnancy can also disrupt fetal development through the passage of inflammatory molecules across the placental barrier. Currently, the effects of the transplacental transfer of maternal inflammation are most robustly established in the field of neurodevelopment. Clinical epidemiological data establish an association between maternal inflammation and an increased risk of neurodevelopmental disorders, such as schizophrenia and autism spectrum disorders [79]. Preclinical studies have been essential to identify possible drivers of these outcomes, demonstrating that maternal inflammation can cause generalized changes to fetal white matter, hippocampal development, increased microglial activation, and altered development of neuronal signaling pathways [80, 81]. Central to these mechanisms is the elevation of maternal inflammatory mediators, specifically cytokines such as interleukin (IL)-6. In the fetal murine brain, transient prenatal IL-6 elevation drives excessive glutamatergic synaptogenesis and brain hyperconnectivity, demonstrating a direct molecular link between a brief maternal inflammatory event and lasting alterations in offspring brain architecture [82]. However, the principles of MIA extend beyond the central nervous system to the training of peripheral organs. For instance, transient maternal infection with the food-borne pathogen Yersinia pseudotuberculosis triggers a surge in maternal IL-6 in mice that crosses the placenta to drive the expansion of IL-17-producing helper T cell (Th17) immunity in the fetal intestine, predisposing the offspring to intestinal inflammation in adulthood [5].

MIA also has the potential to alter the structural architecture of developing organs by prematurely recruiting and activating tissue-resident immune cells. In the developing lung, type 2 immune cells (ILC2 and eosinophils) are required for normal postnatal maturation. However, their premature activation during critical gestational windows can be detrimental to long-term tissue architecture and function. In mice, elevated maternal IL-5 can cross the placenta and promote fetal eosinophilia, which in turn increases airway sensory innervation [83]. This sensory hyperinnervation persists into adulthood, resulting in reflex-mediated airway hyperresponsiveness and a shifted physiological setpoint for allergic disease [83, 84]. The irreversible nature of early-immune activation is further underscored by models of genetic neonatal eosinophilia (via eosinophil-specific SHIP-1 deletion), which demonstrate that early life eosinophil activation elicits damage to airspaces and activates alveolar macrophages that are retained into adulthood, eventually manifesting as a chronic obstructive pulmonary disease (COPD)-like emphysema phenotype in adult mice [85]. Accordingly, early life immune activation (neonatal eosinophilia) may be a predisposing factor to chronic lung disease [86].These preclinical findings provide a pointed example of how transient, maternally-derived inflammatory events can leave a lasting imprint on tissue development and function into adulthood.

Maternal nutrition and dysbiosis

While maternal inflammation presents as acute, transient hits to the developing fetus, maternal nutrition provides a continuous environmental input that shapes fetal immune priming. A growing body of clinical evidence demonstrates that maternal nutritional imbalances during pregnancy drive long-lasting immunomodulatory effects in offspring. For example, maternal vitamin D deficiency is associated with an increased risk of autoimmune diseases in offspring, including multiple sclerosis and type 1 diabetes [87]. Importantly, this nutritional programming must be investigated in the context of gene-environment interactions (further discussed below in Future Directions section). Specific maternal single nucleotide polymorphisms (SNPs) in the vitamin D receptor have been shown to independently influence the offspring’s risk of developing type 1 diabetes, highlighting how maternal genetics contributes to interindividual variability in fetal immune priming [88]. Conversely, maternal consumption of high-fat, high-sugar “Western-style diets” (WSDs) is correlated with a heightened risk of pediatric atopic and inflammatory disorders.

Preclinical models demonstrate that these nutritional factors influence immune ontogeny and act directly on the developing hematopoietic system [89, 90]. Vitamin D is a potent immunomodulator that typically promotes tolerogenic responses. Co-culturing human CD4⁺ T cells with immature monocyte-derived dendritic cells (DCs) pretreated with the active form of vitamin D, 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃) promotes the induction of CD4⁺FOXP3⁺ regulatory T cells in vitro [91]. Vitamin D may also act directly on committed T cells to drive a FOXP3⁺ CTLA-4⁺ regulatory T cell phenotype in the presence of IL-2 [92]. In vivo mouse models illustrate these effects are particularly critical during the prenatal window. Maternal vitamin D deficiency reduces the fetal proportions of lymphoid-biased multipotent progenitor 4 (MPP4) cells and epigenetically shifts hematopoietic gene expression, upregulating leukocyte chemotaxis while downregulating cell maintenance pathways [89]. Strikingly, this programs a persistent reduction of peripheral CD4⁺ and CD8⁺ T cells in male offspring, a defect that remains even if the offspring are placed on a vitamin D sufficient diet postnatally, highlighting a narrow developmental window for nutritional imprinting of fetal progenitor cells.

Conversely, nutritional excess modelled by maternal WSD drives inflammation in offspring. In non-human primate models, chronic maternal WSD exposure skews fetal HSPCs via long-lasting epigenetic reprogramming. Bone-marrow derived macrophages (BMDMs) from these offspring constitutively upregulate genes governing innate inflammatory immune signaling (e.g., TLR1, NFKB1/2), and exhibit a metabolic shift favouring glycolysis over oxidative phosphorylation, a signature of pro-inflammatory activation [90]. An independent study in primates demonstrated that this maternal WSD-exposure persistently alters the offspring’s gut microbiome [93], promoting a dysbiosis that lasts past weaning. Specifically, maternal WSD depleted commensal Campylobacter species in offspring and significantly altered microbial metabolic pathways (including heightened amino acid, carbohydrate and lipid metabolism). This change in the functional capacity resulted in the WSD-exposed offspring’s gut bacteria becoming overly efficient at extracting calories from the diet, a metabolic shift believed to promote adiposity. In parallel murine models, maternal WSD exposure drives a different dysbiotic signature, favouring colonization with gram-negative bacteria and an increased Firmicutes/Bacteroidetes ratio [94] that primes systemic hyperinflammatory responses to endotoxins, marked by elevated production of IL-6, IL-1β, and IL-17A. Additionally, murine pups born to WSD-fed mothers have decreased colonic regulatory T cells and increased baseline intestinal inflammation [94].

The ability of the maternal diet to alter the metabolic capacity of the offspring’s microbiome points to another mechanism of long-term immune imprinting. The gut microbiota functions as an important metabolic regulator, acting to process food, extract nutrients, and synthesize vitamins and metabolites utilized by the host. A large body of evidence suggests that diet, especially one rich in fiber and fermented foods, can modulate the microbiome, which in turn influences the immune system and overall health [95]. While perinatal dietary intervention studies yield variable results due to the inherent diversity of the human microbiome, it is clear that, without microbes present, the host cannot extract all key immunoregulatory nutrients even when consuming a healthy and balanced diet [96]. Perinatal antibiotic treatment therefore serves as a useful model to assess how shifting the early-life microbiome influences pregnancy outcomes [97], and long-term health sequelae for both mother and child [98, 99]. Our lab and others have shown that without key components of the maternal microbiome in the perinatal period, the growing fetus is deprived of transplacentally-transferred metabolites such as short-chain fatty acids (SCFAs) that regulate immune development and inflammation.

The role of microbial derived metabolites in fetal immune development

The longstanding notion that direct microbial exposure is necessary for immune development, education, and maturation is being challenged by emerging research demonstrating that microbial-derived factors, alone, may alter immunity. In humans, the in utero education of the fetal immune system is evidenced by the detection of memory T cells in the fetal intestine, cord blood and placenta. While some recent studies have suggested these cells are primed by a low abundance of live microbes colonizing the fetal environment [100], the concept of in utero colonization remains controversial. Many of these findings are not consistently reproducible, with subsequent analyses suggesting microbial DNA detection in fetal tissues is indistinguishable from background environmental contamination when appropriate experimental controls are used [101]. Rather than direct colonization with microbes, preclinical models have firmly established that maternal microbial metabolites continuously enter circulation and have the capacity to cross the placental barrier to guide fetal hematopoiesis and peripheral immune seeding [102–104]. Thus, the maternal microbiome’s metabolic output, rather than physical microbes, may act as the molecular driver of fetal immune priming.

As an illustrative example, we previously showed that treating pregnant dams with the antibiotic vancomycin depletes intestinal short-chain fatty acid (SCFA)-producing bacteria. Offspring deprived of these maternally derived SCFAs in utero exhibit profound developmental skewing toward T helper type 2 cell (Th2) responses, resulting in exacerbated allergic lung inflammation postnatally [99, 105]. Earlier studies of germ-free mice led to similar conclusions: depletion of a complex perinatal microbiome leads to profound Th2 skewing [6]. Strikingly, this hyper-inflammatory phenotype can be rescued by supplementing the vancomycin-treated mothers with SCFAs in their drinking water, suggesting that transplacental metabolites directly attenuate fetal Th2 skewing via specific T cell- and DC-dependent mechanisms [99].

Furthermore, the specific composition of the maternal microbiome modulates the trajectory of fetal immune development. While perinatal vancomycin drives Th2-mediated allergic asthma, maternal treatment with streptomycin, which depletes a different array of microbes, dramatically increases offspring susceptibility to Th1/Th17-driven hypersensitivity pneumonitis [106]. Together, these data suggest that perturbations to the maternal microbiome create specific metabolic voids in utero, shifting fetal immune development to predispose the offspring to different types of inflammatory disease later in life. Moving forward, cross-fostering experiments in mice and tightly controlled longitudinal human cohorts are needed to definitively disentangle these in utero metabolic effects from the profound immune education that occurs immediately postnatally when the newborn is directly colonized by maternal flora [107].

Layered hematopoiesis and developmental window specific vulnerability

The impact of prenatal environmental cues, whether inflammatory, nutritional or microbial, is largely dictated by the specific developmental wave they intercept. Nearly all subsets of immune cells develop via “layered hematopoiesis”, where distinct waves of progenitors arise at different embryonic stages, conferring unique and often lifelong functional properties to the mature cells (Fig. 2). Consequently, early life environmental exposures can permanently shape tissue-resident immunity by selectively altering these restricted developmental waves [105, 108]. Similarly, interventions to rescue the effects of early-life immune skewing are also temporally restricted [99].

Fig. 2.

Lifelong persistent and functional divergence of immune cell subsets arising from distinct developmental waves. Immune cells arise in temporally distinct waves during fetal (blue), neonatal (green), and adult (orange) life. Each wave contributes subpopulations of cells with unique functional programs. In adult tissues, most immune cells are of adult origin, but select subsets of fetal and neonatal-derived cells persist as is seen in some tissue specific macrophage, innate lymphoid cell and T cell populations (dotted box). Upon tissue insult (red arrow), these co-existing populations may participate differently in the ensuing immune response shown schematically: from an evolutionary lens, fetal and neonatal-derived cells are better poised as rapid responders with broader functions, whereas adult-derived cells mount delayed but highly antigen-specific and robust responses. Understanding whether developmental origin influences immune cell function is key to decoding immune responses across the lifespan

In the developing lung, for example, tissue-resident populations of group 2 innate lymphoid cells (ILC2) are established during a strictly timed perinatal wave. In mice, these early-life ILC2s undergo a physiological burst of expansion during the “first breath”, driven by the release of epithelial-derived alarmins like IL-33 [109, 110]. Neonatal ILC2s trained by this specific perinatal alarmin signal persist into adulthood and remain intrinsically more responsive to subsequent IL-33 stimulation than ILC2s derived later from adult bone marrow [11]. Disruptions during this critical “first breath” window can permanently alter the lung’s inflammatory setpoint.

The clinical consequences of targeting specific developmental waves are further illustrated by the ontogeny of mast cells. Tissue-resident mast cells display great diversity based on their embryonic origins. Connective tissue mast cells originate from yolk-sac-derived erythromyeloid progenitors, whereas mucosal mast cells are predominantly HSC-derived [45]. Recent murine studies demonstrate that maternal prenatal stress (PS) alters the programming of the early yolk-sac derived wave of mast cells that seed fetal skin [111]. In PS offspring, these cells are highly activated and degranulate at steady state, causing the pups to develop severe, eczema-like skin lesions in response to mild mechanical irritation. However, this eczematous phenotype naturally resolves by 24 weeks of age. Fate-mapping demonstrates that by this adult stage, the hyper-reactive yolk-sac-derived mast cells have been entirely replaced by a new, unaffected wave of HSC-derived cells [111]. This transient but severe yolk-sac driven window of vulnerability likely increases epicutaneous sensitization to environmental antigens early in life, providing a mechanistic explanation for the atopic march, where early pediatric eczema acts as a gateway to subsequent allergic asthma and food allergies [112, 113].

A similar developmental division of labor also exists within the adaptive immune compartment. Fetal-derived naive CD8⁺ T cells are intrinsically different from their adult counterparts, preferentially adopting a “virtual memory” phenotype and acting as early, rapid, innate-like effectors [13, 114]. Conversely, adult-derived naive CD8⁺ T cells exhibit slower kinetics but generate highly specific, long-lived memory responses. Using molecular “time-stamping” to profile these prenatal versus adult waves of other immune cells and their relevance in human tissues represents an exciting future direction for the field. While retrospectively distinguishing fetal-origin cells in adult humans is challenging, adaptive cells may offer a unique molecular footprint. Fetal progenitors have lower expression of terminal deoxynucleotidyl transferase (TdT), thus fetal-derived T cells are generated with fewer N-nucleotide additions resulting in shorter and less diverse T cell receptor (TCR) junctions [115]. Leveraging TCR junctional diversity analysis could be a valuable approach to identify the persistence of fetal-origin T cells in adult homeostatic and diseased tissues [74, 116]. Understanding whether these long-lived, prenatally-programmed clones contribute to aberrant responses in chronic inflammatory diseases remains a critical frontier in translational immunology.

The in utero environment as a prenatal training ground

These diverse factors, from maternal infections and systemic inflammation to microbial-derived metabolites, collectively suggest that the in utero environment functions as a “prenatal training ground.” Here, the developing immune system is conditioned by vertically transferred cues, providing a sheltered opportunity for the fetus to preview future challenges, begin shaping immune responses and establish regulatory setpoints while under maternal protection.

The developmental stage at which a fetus encounters these signals profoundly shapes the resulting immune outcomes. For example, fetal B cells are capable of mounting Plasmodium falciparum (Pf)-specific responses as early as 22 weeks of gestation in humans, but the quality of the immunoglobulin response is dictated by timing [117]. Preterm newborns exposed to Pf antigens earlier in gestation show higher odds of generating IgM, whereas B cells from term newborns display evidence of class switching to IgG, consistent with a more mature capacity for effector cell engagement. Similar temporal-dependent outcomes apply to maternal interventions as well. Neonates of mothers vaccinated with the H1N1pnd09 vaccine during pregnancy generate increased transforming growth factor beta 1 (TGF-β1) [118]. This effect is enhanced the earlier the vaccines are administered in pregnancy. Elucidating how the precise gestational timing of these prenatal exposures sculpts divergent health outcomes will be key to balancing immune maturation with protection from chronic inflammatory disease.

Limitations and translational gaps

The mechanistic insights from preclinical models are foundational to our understanding of fetal immune programming, but translating these findings to preventative health strategies requires navigating significant biological and methodological limitations.

Cross-species developmental alignment

The temporal effects of immune development and permissive windows of modulating immune function gleaned from murine models must be interpreted cautiously. Common animal models differ markedly from humans in gestational length and immune ontogeny. For example, newborn mice are still undergoing waves of immune development after birth that are largely completed prenatally in humans. Many important fetal immune milestones (e.g., thymic development, transplacental IgG transfer or maturation of dendritic cells), occur on different schedules in mice versus humans (Table 3) and, accordingly, mapping the windows of vulnerability in mice to human trimesters requires careful developmental alignment. Those caveats aside, in all species, the prenatal period is a unique window of immune education and defining these windows across models will be essential for translation of fetal immune programming studies.

Heterogeneity of evidence and phenotypic convergence

A significant limitation of current human perinatal immune profiling studies is the focus on phenotypic frequencies rather than functional readouts. Olin et al. demonstrated that while very preterm and term babies have striking different cord-blood immunophenotypes at birth, these differences rapidly converge onto a shared trajectory by 3 months of age [119]. However, phenotypic convergence does not guarantee functional equivalence. Preterm infants carry distinct risks later in childhood and develop asthma more frequently and atopic dermatitis less frequently than term born counterparts [120]. Similarly, Kamdar et al. showed that while preterm babies can phenotypically “catch up”, specific defects, such as lower frequencies of CXCL8-producing T cells following perinatal inflammation, persist and precede worse clinical outcomes [121]. This suggests that two infants whose cell counts look similar by one year may nonetheless differ in cytokine responsiveness, regulatory setpoints or memory potential later in life. Future studies should prioritize functional assays, and epigenetic and metabolic profiling, as early-life immune reprograming may only manifest when immune cells are challenged later in life.

Future directions: longitudinal cohorts and addressing interindividual variability

The recognition of a layered immune system offers a paradigm-shifting perspective on chronic disease: many adult-onset chronic diseases may not be adult-onset in their etiology, but rather adult-manifesting. To advance this concept beyond compelling findings from animal models, future clinical research must incorporate the complexity of immune ontogeny into human study design. Characterizing these developmental immune trajectories requires capturing the complete fetal exposure landscape (the fetal “exposome”). Practically, this can be achieved by leveraging routine maternal exams during pregnancy for serial biospecimen collection. For example, isolating placenta-derived extracellular vesicles and metabolomic profiling of maternal blood may offer a powerful, minimally invasive approach to monitor real-time fetal-maternal immune crosstalk without disturbing pregnancy.

Fetal immune development is a product of multiple environmental factors. Beyond maternal health and nutrition, parental genetics, exposure to environmental pollutants and socioeconomic status are additional determinants of offspring health. Genes and environmental exposures cooperatively influence disease risk, and this interindividual variability should be explored in perinatal health research. The use of genetically identical animal models has isolated specific biological mechanisms of fetal immune imprinting, however many of these models inherently bypass the complex gene-environment interactions that define human health. In a genetically diverse human population, the exact same maternal infection can induce vastly different levels of maternal immune activation and subsequent offspring immune responses depending on the host’s specific genetic architecture. Genetic background influences how an exposure is translated to the developing fetus through factors such as the cytokine milieu and placental permeability. Expanding the scope of clinical research to include these multifactorial factors is important to avoid reductionist frameworks that place undue burden or blame solely on maternal behaviours / choices [122]. However, avoiding “mother blaming” should not equate to ignoring the maternal-fetal interface. Instead, we hope this narrative review encourages the medical community to view pregnancy not as a transient physiological event, but as a highly modifiable therapeutic window.

Prioritizing and funding longitudinal birth cohorts that pair robust clinical data with serial multi-omics may yield new translational insights into early-life determinants of long-term immune function. Prospective cohorts that follow mother-child pairs from pregnancy throughout childhood, and ideally into adulthood, are crucial to unravel the types of exposures and developmental windows raised here. Canadian-led initiatives, such as the Canadian Healthy Infant Longitudinal Development (CHILD) Study and the Genetics of Glucose regulation in Gestation and Growth (Gen3G) cohort, provide opportunities to connect prenatal environmental, dietary and clinical data with serial postnatal immune and metabolic profiling. Carefully crafted cohort studies allow for the identification of modifiable risk factors including nutrient levels, microbiome composition or timing of maternal vaccinations that associate with healthier immune trajectories.

In practice, this will require integrating detailed immunophenotyping (e.g., immune cell subsets, cytokine responses, and epigenetic marks) with clinical and environmental data in existing and new cohorts. National birth cohort initiatives such as the CHILD, ALSPAC, COPSAC, MoBa and ECHO consortia, as well as hospital-based pregnancy trials should consider incorporating immune trajectories and endpoints alongside traditional outcomes. Notably, the ongoing FeFiFo-MOMS trial is designed to examine how high-fiber and fermented food interventions during pregnancy influence maternal gut microbiota diversity, its transmission to infants and subsequent implications on metabolic and immune health [123]. While the results are not available yet, FeFiFo-MOMS represents a pioneering step toward intervention-based prenatal immunomodulation.

With the advent of powerful tools such as spectral flow cytometry, single-cell sequencing, spatial transcriptomics and epigenetic profiling, it is now possible to chart lifelong immune trajectories beginning in utero. Mapping how maternal environments and exposures shape these trajectories will help identify critical windows and targets for intervention. Ultimately, longitudinal studies are needed to translate our understanding of developmental immunology into preventative public health strategies that reduce the incidence of allergies, autoimmunity and other chronic diseases by supporting immune development from its earliest stages and prioritizing maternal health as the foundation of lifelong immunity.

Abbreviations

AGM

Aorta gonad mesonephros

APC

Antigen-presenting cell

BMDM

Bone marrow derived macrophage

cDC

Conventional dendritic cell

CHILD Study

Canadian Healthy Infant Longitudinal Development Study

COPD

Chronic obstructive pulmonary disease

DC

Dendritic cell

DOHaD

Developmental Origins of Health and Disease

Eos

Eosinophils

eMPP

Embryonic multipotent progenitors

HSC

Hematopoietic stem cell

HSPC

Hematopoietic stem and progenitor cell

ILC

Innate lymphoid cell

MIA

Maternal immune activation

MPP4

Multipotent progenitor type 4 (lymphoid-biased)

MS

Multiple sclerosis

NK

Natural killer cell

pDC

Plasmacytoid dendritic cell

PF

Plasmodium falciparum

PN

Postnatal

PS

Prenatal stress

SCFA

Short-chain fatty acid

SHIP-1

SH2 domain-containing inositol 5’ phosphatase-1

SLE

Systemic lupus erythematosus

T1DM

Type 1 diabetes mellitus

TGF-β1

Transforming growth factor beta 1

WSD

Western-style diet

Authors’ contributions

SC conceptualized the review, analyzed relevant literature and drafting the original manuscript with the support of NM and MB. KMM supervised the project, acquired funding that supported this work and provided guidance. All authors participated in the review and editing process and approved the final manuscript.

Funding

The authors declare financial support was received for the research and/or publication of this article. The authors are supported by the Canadian Institute of Health Research (CIHR) grants (PJT-518208 and PJT-4488212) and the Canadian Microbiome Team grants (MRT-168048 and MRT168044). SC is supported by a CIHR Vanier Scholarship. NM is supported by a Faculty of Medicine at the University of British Columbia Summer Studentship.

Data availability

Not applicable.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.