Pregnancy depends on a state of maternal immune tolerance mediated by CD4+ regulatory T (Treg) cells. Uterine Treg cells release anti-inflammatory factors, inhibit effector immunity, and support adaptation of the uterine vasculature to facilitate placental development. Insufficient Treg cells or inadequate functional competence is implicated in infertility and recurrent miscarriage, as well as pregnancy complications preeclampsia, fetal growth restriction, and preterm birth, which stem from placental insufficiency. In this review we address an emerging area of interest in pregnancy immunology–the significance of metabolic status in regulating the Treg cell expansion required for maternal–fetal tolerance. We describe how hyperglycemia and insulin resistance affect T cell responses to suppress generation of Treg cells, summarize data that implicate a role for altered glucose metabolism in impaired maternal–fetal tolerance, and explore the prospect of targeting dysregulated metabolism to rebalance the adaptive immune response in women experiencing reproductive disorders.

The events of conception and embryo implantation challenge the immune response in a unique way. Within days of conception, the embryo attaches to the uterine lining and commences a finely controlled developmental program (1). Almost immediately, trophoblast cells harboring the embryonic genome and so expressing paternally inherited fetal alloantigens make direct contact with maternal tissues and commence proliferating, differentiating, and invading into the lining of the uterus to ultimately form a mature placenta that sustains fetal growth until birth.

This impressive feat occurs despite clear evidence that the mother’s immune response recognizes and becomes activated toward fetal alloantigens and other minor histocompatibility Ags expressed by placental and fetal cells (24). Early thinking that immune evasion or systemic immune suppression must explain maternal–fetal tolerance (5) has been proven incorrect, and we now understand that the uterus is not “immune-privileged” and the woman’s immune response is not suppressed in pregnancy. Indeed, abundant immune cells reside in the uterus in close contact with infiltrating trophoblasts and actively participate in many aspects of establishing, sustaining, and terminating pregnancy (6, 7).

To allow fetal and maternal cells to coexist, a range of specialized mechanisms mediate an active state of maternal–fetal tolerance (8, 9) that involves substantial adaptations in both the innate and adaptive immune cells and mediators in the uterus and, to some degree, systemically. Within the adaptive immune compartment, a crucial feature is the T cell response to conceptus Ags and a comprehensive bias to promote generation of CD4+ regulatory T (Treg) cells and suppress generation of Th1 and Th17 effector T (Teff) cells (1012). Treg cells exert a range of functions in the decidua to inhibit effector immunity, control inflammation, and promote maternal vascular adaptations required to support trophoblast invasion and placental access to the maternal blood supply (9, 13, 14).

The skew toward a Treg cell bias that enables pregnancy tolerance is facilitated by attenuated trophoblast expression of polymorphic MHC molecules (7, 15, 16); placental release of anti-inflammatory and protolerogenic hormones, cytokines, and immune modulators (1719); and formation of the decidua, a compartment of the uterus that interfaces with the placenta wherein the stromal fibroblasts undergo specialized differentiation to tightly regulate immune cell access and egress (20, 21). Together, these features promote sequestration of Treg cells and associated immune cells that favor placental development and function, and they limit effector T cell activity to ensure that the placenta is not exposed to potentially destructive elements of the maternal immune response.

Treg cells engage with a range of innate immune cells that are abundant in the decidua at implantation, particularly macrophages (22), dendritic cells (DCs) (23, 24), and unique populations of innate lymphoid cells (25), notably including NK cells with a CD56hiCD57lo phenotype (uterine NK [uNK] cells) (25, 26). These innate immune cells acquire anti-inflammatory phenotypes in response to Treg cell– and uNK cell–mediated modulation working in concert with progesterone and unique trophoblast-derived signals (27, 28). When their phenotypes are properly attuned, they promote placental development through secreting growth factors and modifying the uterine vasculature to support trophoblast invasion (29). The result is multilayered and cross-reinforcing protection for the placenta and fetus against injury from inflammatory agents and immune cells that can otherwise compromise fetal survival and growth (9, 30, 31).

Understanding how the T cell shift underpinning pregnancy tolerance is established, as well as the genetic, physiological, and environmental factors that influence its success, is an important research goal with a pressing clinical imperative. An altered maternal immune response is implicated as a causal or contributing factor in many common reproductive conditions, as well as pregnancy disorders that emerge later in gestation due to abnormal placental function (32, 33). The reproductive disorders with an immune etiology include recurrent implantation failure (also known as idiopathic infertility), wherein overtly healthy embryos fail to implant in repeated menstrual cycles, which occurs in at least 10% of women seeking in vitro fertilization treatment (34), and recurrent miscarriage, defined as loss of two or more pregnancies before 20 wk of gestation (excluding ectopic and molar pregnancies), which occurs in ∼1–2% of women (35). The pregnancy disorders that involve the maternal immune response include preeclampsia, which affects 3–5% of pregnancies (32) and is a major cause of morbidity and mortality for women and infants, particularly in low- and middle-income countries; fetal growth restriction, where the fetus fails to grow at a sufficient rate; and preterm birth, which affects 5–15% of all pregnancies and is the top-ranked reason for child death, killing >1 million infants annually (36, 37).

There are extensive data linking insufficient Treg cell numbers and/or inadequate Treg cell functional competence during embryo implantation and early placental development with each of the above reproductive and pregnancy disorders (14, 31, 38). These conditions typically have an inflammatory pathophysiology and are accompanied by proinflammatory phenotypes in uterine immune cells of both the innate and adaptive compartments, especially a counteractive increase in Teff cells. Elevated numbers of Th1 and/or Th17 cells, as well as accompanying increases in inflammatory cytokine production, are particularly evident in recurrent miscarriage (3941) and preeclampsia (42, 43). Compelling evidence that Treg cell deficiency is a cause, not a consequence, of pregnancy loss comes from animal models (10, 4446). An underlying T cell etiology in women is supported by data indicating that prior sexual and reproductive history influences pregnancy outcomes (47), and of couple-specific, HLA-linked dispositions to reproductive conditions (48, 49), consistent with a protective effect of adaptive immune “memory” to partner histocompatibility Ags.

Whether there will be sufficient Treg cell tolerance to sustain a healthy pregnancy depends on events around conception and in early pregnancy, when the T cell response to paternally derived alloantigens commences. At this time, a complex dialogue involving maternal, paternal, and conceptus-derived signals interact with female sex hormones to stimulate expansion of the Treg cell pool and to elicit Treg cell recruitment into gestational tissues (13, 50). The abundance and phenotype of decidual Treg cells can vary extensively in size and quality (51, 52) depending on a range of endogenous and external factors (31, 53).

A key goal of research in reproductive immunology is thus to understand the factors and mechanisms that control generation of sufficient Treg cells to support pregnancy tolerance and enable optimal placental development and function. One emerging area of focus is the significance of metabolic factors in skewing T cell phenotypes and causing Treg cell insufficiency in pregnancy. There has been a dramatic world-wide increase in obesity, type 2 diabetes, and prediabetic states of hyperglycemia and insulin resistance during recent decades (54). Increasingly, metabolic factors, especially glucose levels, are implicated in T cell phenotype commitment and stability (5557). That glycemic dysregulation is common in fertility disorders (58, 59) raises the prospect that poor glucose control contributes to Treg cell deficiency in some women. In this brief review we describe current understanding of how Treg cells are modulated by glucose metabolism and how this may contribute to fertility and pregnancy disorders, and we raise the prospect of targeting metabolic status to rebalance the adaptive immune response where immune dysregulation is implicated.

Uterine recruitment of Treg cells in preparation for conception commences in the proliferative phase of each cycle, with an estrogen-driven peak in the peri-ovulatory phase (60). After further expanding in early pregnancy, decidual Treg cells remain elevated through the course of gestation and then decline just prior to birth (52, 61, 62). At their peak in early pregnancy, T cells make up 10–20% of the resident leukocytes in the first trimester (63), and ∼10–30% of the CD4+ T cells are Treg cells as defined by expression of the FOXP3 transcription factor (52, 61, 64). This is a substantial enrichment compared with peripheral blood; in contrast, the frequency of decidual Th1 cells is only slightly higher than blood whereas Th17 and Th2 cells are comparable in proportion. This balance is consistent with a mild inflammatory environment controlled by Treg cells (61, 65). The decidual Treg cells have phenotypes indicating both thymic and peripheral (pTreg) origin, and there is considerable phenotypic heterogeneity that varies across pregnancy stage (6668).

The critical time for determining availability and functional competence of Treg cells for pregnancy tolerance is the preconception and periconception phase. Priming and expansion of Treg cell subsets commence in the menstrual cycle in which conception occurs. Mouse studies show that seminal fluid contact plays a key role in establishing the Treg cell pool (69, 70). The estrogen-dominated environment in the peri-ovulatory phase provides a window of opportunity for priming and activation of the T cell response to the conceiving partner’s alloantigens delivered in seminal fluid (71). Seminal fluid contains potent immune-regulatory and tolerance-inducing factors, notably TGF-β, E-series PGs, and microRNAs (72, 73). At coitus, these factors elicit induction of cytokines and chemokines in the cervical epithelium, including IL-1B, IL-6, IL-8, and CSF2 (74, 75), which results in recruitment of both innate and adaptive immune cells into the tract in an inflammation-like response. Uterine macrophages and DCs take up seminal fluid Ags and traffic to draining lymph nodes, where they prime T cells to generate an expanded Treg cell pool (71). In turn, these Treg cells are recruited via the peripheral blood circulation into the endometrium, in response to chemotactic factors such as CCL19 (76), where they are positioned to modulate inflammation, promote uterine receptivity to embryo implantation, and stimulate the vascular changes required to support placentation (45). Once implantation commences, there is further opportunity for Ag-mediated stimulation of resident Treg cells (71). The significance of Ag exposure for stimulating Treg cell proliferation and ensuring sufficient effector function at implantation is evidenced by studies in abortion-prone mice. Transfer of Treg cells from pregnant donor mice is effective in reducing fetal loss in the abortion-prone strain, whereas Ag-inexperienced donor Treg cells from nonpregnant mice are ineffective (77). Given that Treg cell effector function is commonly understood to be Ag independent, this likely reflects the effect of seminal fluid factors on promoting Treg cell proliferation and acquisition of epigenetic changes that elevate their suppressive potency (78), and/or the effect of progesterone exposure on embedding Treg cell phenotype stability (79).

The extent and quality of the Treg cell response for the duration of pregnancy is largely determined by events during this inductive phase (31, 50). There are a variety of factors that can modify the strength and quality of the uterine Treg cell response. Contact with paternal and conceptus alloantigens must occur under conditions that favor stable Treg (not Teff) cell development, and largely this depends on cytokine regulation of the phenotypes of APCs. A tolerogenic phenotype is imposed on uterine DCs by TGF-β, GM-CSF, IL-10, galectin-1 and PGE (27, 80, 81). Treg-derived IL-10, TGF-β, and HO-1 induce tolerogenic DCs and M2 macrophages to express IDO and sustain pTreg generation (8284). Decidual Treg cells also express CTLA4 (61, 85), which downregulates DC costimulatory molecules CD80 and CD86, needed for Teff activation (86). Trophoblasts reinforce the tolerogenic DC phenotype and drive local Treg differentiation by inducing DC production of the cytokine thymic stromal lymphopoietin (TSLP) (87).

The reason why some women have insufficient Treg numbers and function is likely to relate to altered events in pre- and peri-conception priming of the Treg cell response. Most T cells in the human decidua have a memory phenotype (CD45RA or CD45RO+) (88, 89), consistent with regular restimulation with male partner’s seminal fluid Ags. HLA-C is the only polymorphic HLA expressed in human trophoblasts, and fetal–maternal HLA-C mismatch is associated with elevated decidual Treg cells (3) and maternal protection from preeclampsia (49). Many decidual Treg cells show fetal HLA-C Ag specificity (64, 90), but specificity to reproductive and other Ags has not been evaluated. Whether there is altered turnover of Treg cells in pregnancy disorders has not been investigated, other than one recent study suggesting that in women with preeclampsia, reduced placental of the Treg cell survival factor galectin-2 (Gal-2) may result in increased Treg cell death and contribute to reduced frequency of Treg cells (91).

Treg cell priming may be dysregulated in some women due to seminal fluid composition or Treg cell responsiveness to seminal fluid signals (38, 92). For example, when CD4+ cells from recurrent miscarriage patients are cultured with DCs and the partner’s seminal fluid Ags, CD4+IL-17+ and CD4+IFN-γ+ cells proliferate excessively and fewer CD4+CD25+Foxp3+ Treg cells are generated, compared with fertile controls (93). The composition of seminal fluid immune-regulatory agents, particularly protolerogenic TGF-β, varies between men and within men over time (94). The seminal fluid of some men contains the antitolerogenic cytokine IFN-γ, which drives generation of Th1 immunity, particularly in the event of genital tract infection (9597). IFN-γ interferes with synthesis of CSF2 required to drive T cell activation at conception (81, 98), skew Th0 differentiation toward Th17 cells (99, 100), and cause Treg cells to transdifferentiate (101).

Bioavailability of cytokines, hormones, and microRNAs and the reproductive tract microbiome in the conception environment all potentially influence the peri-conception Treg cell response (102104). IL-10 deficiency at implantation causes an unstable Treg response, with more rapid phenotype conversion and reduced capacity to withstand an inflammatory challenge in later gestation (105, 106). Progesterone bioavailability impacts the Treg cell phenotype and is correlated with secure fate commitment (107, 108), in part by inducing galectin-1 to reinforce the tolerogenic DC phenotype (80). Within hyperinflammatory environments, pTreg cells exhibit phenotypic plasticity and lineage instability, and they can shift phenotype to express Teff cell cytokines (101, 109). Treg cells that undergo transdifferentiation to effector Th1 or Th17 cells, known as exTreg cells, drive pathology in inflammatory and autoimmune conditions (110, 111).

There is evidence implicating Treg phenotype instability in reproductive disorders. Defects in stability would explain the observations of reduced Treg suppressive competence (112) and evidence of elevated Th1 and Th17 cells in preeclampsia (42, 43). An intrinsic deficiency in peripheral blood Treg cells in recurrent miscarriage is indicated by diminished IL-2 and TGF-β secretion, as well as reduced IL-2/STAT5 signaling (113), whereas decidual Tregs have elevated IFN-γ expression (114). Genetic factors also contribute; for example, Treg cells that express insufficient FOXP3 due to gene polymorphisms in the promoter region of FOXP3 are inherently more phenotypically plastic and prone to express inflammatory cytokines in the context of preeclampsia (115).

There is substantial evidence that the metabolic pathways used by T cells influence their commitment to a proinflammatory or protolerance function, implying that metabolic perturbations might affect Treg cell frequency and be a cause of reduced Treg cells in various pathological conditions (5557). Naive T cells are metabolically quiescent, having low energy requirements, whereas nonproliferating conventional T (Tconv) cells rely on fatty acid oxidation (116). Upon activation by ligation of the TCR, T cell proliferation and gain of effector function increase energy demand. This results in a shift to a high rate of aerobic glycolysis (117), which provides most of the cell’s energy, as well as increased rates of oxidative phosphorylation and glutaminolysis (118). This shift is particularly evident in proinflammatory Th1 and Th17 cells, which upon TCR engagement take up glucose via glucose transporter 1 (GLUT1), the major glucose transporter on T cells, leading to glucose catabolism to pyruvate and ATP production (119121).

The level of activity of the glycolytic pathway is a critical factor that determines the phenotypic lineage for Th1 and Th17 T cells (122, 123). However, anti-inflammatory Treg cells rely less on glycolysis to produce energy and instead synthesize a greater proportion of their ATP through fatty acid oxidation and oxidative phosphorylation (116, 120, 124, 125). Indeed, inhibition of oxidative phosphorylation or fatty acid oxidation reduces Treg cell suppressive capacity (126, 127). Proteomic analysis of human Treg and Tconv cells showed two different profiles upon in vitro activation, with proliferating Tconv cells mainly relying on glucose metabolism, and Treg cells using both glycolysis and fatty acid oxidation (116).

Immune and metabolic function are inherently linked, and glucose metabolism is paramount (57). TCR ligation and CD28 costimulation provoke an increase in the signaling molecule mammalian target of rapamycin (mTOR), which is the key component of two protein complexes, mTORC1 and mTORC2, and a principal driver of glycolysis in T cells (128). mTOR drives an increase in membrane GLUT1, allowing more glucose to enter the cell (129). The central role of mTOR in regulating T cell phenotypic fate can be demonstrated in mouse T cell experiments where genetic deficiency in mTOR alters the balance of phenotypic lineages in proliferating T cells. Upon stimulation in Th1 polarizing conditions, T cells lacking mTOR have low expression of the phenotype-defining cytokines IL-2, IFN-γ, and TNF, and they do not upregulate the Th1 hallmark transcription factor, T-bet (130). Likewise, Th17 polarizing conditions fail to skew mTOR-deficient T cells toward a Th17 phenotype characterized by expression of IL-21 and retinoic acid–related orphan receptor (ROR)γt (130). Instead, these cells acquire a suppressive, FOXP3-expressing Treg cell phenotype (130). An increase in mTORC1 promotes transcription and translation of hypoxia inducible factor 1α (HIF-1α) (131), in turn inducing a suite of genes including GLUT1 that stimulate glycolysis over oxidative phosphorylation (132). HIF-1α also induces expression of the key Th17 transcription factor RORγt, driving T cells to a proinflammatory fate (125, 133). HIF-1α–regulated glycolysis is critical for Th17 cell generation (125, 133) with HIF-1α deficiency or inhibition of the HIF-1α pathway constraining glycolysis and shifting the Th17/Treg balance toward anti-inflammatory Treg cells (125).

Glutaminolysis is a key mechanism for energy production in T cells. Glutamine is readily taken up by activated T cells via the transporter molecule neutral amino acid transporter B(0) (ASCT2). T cell deficiency of ASCT2 prevents glutamate uptake and mTORC1 activation and thus the development of Th1 and Th17 proinflammatory cells (134). Glutamate metabolism activity prevents Treg cell development, with metabolites leading to heavy methylation at the FOXP3 locus, thus blocking transcription of this key Treg cell transcription factor and preventing Treg cell generation (135).

The availability of alternative energy supplies can therefore substantially influence the development and phenotype of activating T cells. As glycolysis favors proinflammatory T cells, glucose deprivation causes reduced expression of proinflammatory cytokines such as IFN-γ (136138), and a shift in T cell differentiation toward a Treg cell profile (119, 125). Conversely, CD4+ T cells activated in glucose-rich environments have increased expression of proinflammatory cytokines, including IL-1β, IL-6, and TNF (139).

Excessive nutrient intake can also cause dysfunction of the mitochondria that carry out the conversion of nutrients to energy downstream of glycolysis or β-oxidation of fatty acids (140). A consequence of mitochondrial dysfunction is elevated reactive oxygen species leading to oxidative stress. Elevated mitochondrial oxidative stress has been associated with Treg cell death in autoimmune diseases and may be a contributing factor to the Treg cell deficiencies commonly seen in those conditions (141).

In summary, hyperglycemia has the potential to skew the energy source driving the T cell pool, to change the Th17/Treg cell balance, and to lead to increased proinflammatory cytokine synthesis and reduced Treg cell number and/or function. This outcome is seen in individuals with type 2 diabetes or insulin resistance, who have more Th17 cells and a reduced number and function of Treg cells (142, 143).

T cell metabolism has become an area of intense investigation in several clinical settings, particularly in metabolic disorders such as type 2 diabetes and prediabetic hyperglycemia. Changes in metabolic function lead to chronic, low-level inflammation (144), which in turn reduces insulin signaling, subsequently increasing insulin resistance (145). Insulin resistance leading to hyperglycemia thereby has the potential to skew the energy source driving the T cell pool, changing the Th17/Treg cell balance toward proinflammatory T cells (146).

There is compelling evidence for a shift toward a proinflammatory state in individuals with hyperglycemia, as shown by a meta-analysis of 91 studies concluding that type 2 diabetes patients have a proinflammatory skewing of the immune response, with reduced abundance of Treg cells and increased serum concentrations of TNF and IL-6 (142). This skewing of the T cell balance is evident in both type 2 diabetes and insulin-resistant patients, and it is characterized by both more Th17 cells and a reduced number and function of Treg cells (142, 143). Treg cells recovered from hyperglycemic donors exhibit reduced IL-10 synthesis and impaired suppressive capacity (147). Analysis of the Treg cell pool in type 2 diabetes patients shows an increase in IL-17 expression that is positively correlated with glycated hemoglobin and body mass index, and negatively correlated with Treg cell IL-10 production (143). Again, there is a functional consequence with Treg cells exhibiting a decline in their suppressive capacity (143).

In mouse models hyperglycemia results in hyperresponsiveness of proinflammatory T cells to TCR stimulation, causing T cells to produce excessive cytokines and thereby amplify the chronic inflammation associated with glucose dysregulation (148). As well as impacts on glucose availability, this is likely to be partly due to direct effects of insulin on Treg cells, as Treg cells express the insulin receptor and hyperinsulinemia impairs Treg cell synthesis of IL-10 and suppressive capacity (147).

Immunometabolic regulation is also seen in other proinflammatory disease states, including cancer. Tumors generally have a high rate of glycolysis leading to elevated lactate, which inhibits T cell effector function. This lack of glucose availability can enhance the Treg cell response within the tumor, leading to a protolerance environment that promotes tumor growth (149). Inflammation driven by infection can lead to insulin resistance and hyperglycemia, which provides abundant glucose to facilitate further activation and proliferation of proinflammatory T cells (150).

In a healthy pregnancy there is a characteristic shift in peripheral blood immune cell metabolism, with a decline in glycolysis compared with nonpregnant women (151). Presumably this contributes to the characteristic suppression of Th1 and Th17 cells that occurs in pregnancy to constrain the availability of Teff cells that may threaten pregnancy success. In pregnant women with hyperinsulinemia brought about by insulin resistance, this shift in immune balance may be impaired. Given that elevated glucose availability acts to constrain development of anti-inflammatory Treg cells and instead promotes proinflammatory Th1 and Th17 T cells, increased proinflammatory Th1 and Th17 cells could arise through both direct effects and indirect effects of reduced Treg cells.

There is some evidence supporting the postulate that T cell perturbation is a mechanism linking uncontrolled glucose with pregnancy complications. This includes findings of elevated release of proinflammatory cytokines TNF and IL-6 from peripheral blood leukocytes in pregnant women with hyperinsulinemia (152). Gestational diabetes, which causes hyperglycemia, is a common metabolic disorder of pregnancy with a rising incidence (153). Unless blood glucose is appropriately controlled, gestational diabetes increases the likelihood of miscarriage and pregnancy complications, including preterm birth. Consistent with a T cell–mediated mechanism, the insulin resistance and hyperglycemia seen in gestational diabetes are associated with a marked reduction in the suppressive capacity of peripheral blood Treg cells (154). Gestational diabetes also changes the naive and memory phenotype of the Treg cell pool, with a decreased proportion of naive Treg cells (154).

Evidence that elevated blood glucose can cause Treg cell changes in pregnancy disorders comes from studies in mice. Mice in which a diabetic state is induced by streptozotocin have an impaired T cell response to conception and pregnancy. Notably, examination of the T cells in the lymph nodes draining the uterus showed that peripheral Treg cells (defined as neuropilin-1–negative Treg cells) were differentially impacted, being 60% fewer in number than peripheral Treg cells in control mice. The reduction in Treg cells was accompanied by increased uterine expression of proinflammatory cytokines TRAIL, IL-6, and TNF, as well as reduced rates of embryo implantation and fetal development (155).

Consistent with a proinflammatory effect of hyperglycemia contributing to pregnancy loss, a small study has shown that women experiencing recurrent miscarriage and having diagnosed metabolic syndrome have greater expression of proinflammatory cytokines, including IL-1β, IL-6, IL-17, and TNF, than do recurrent miscarriage patients without metabolic syndrome (40). This change in cytokine levels is accompanied by an altered T cell response, with more Th17 cells and fewer Treg cells when metabolic syndrome is diagnosed (40). This finding supports the hypothesis that insulin resistance and/or hyperglycemia change the T cell profile toward a proinflammatory response that is incompatible with healthy pregnancy, with the potential to lead to fetal loss or later onset complications of pregnancy.

Both fasting insulin and insulin resistance have been found to be greater in recurrent miscarriage patients (156, 157). Even within nondiabetic patients, hyperinsulinemia is very common (58). A significantly higher prevalence of β cell dysfunction and abnormal glucose metabolism is reported in nondiabetic recurrent miscarriage patients compared with women with healthy pregnancies (59). This finding suggests that the Treg cell changes reported in women with recurrent miscarriage may often be linked to an underlying metabolic disorder.

There are environmental and nutritional factors that interact with metabolic status to affect Treg cells. Hyperinsulinemic women experiencing recurrent miscarriage commonly also have vitamin D deficiency (58). Meta-analysis shows that a low vitamin D level is associated with a 45% increased risk of the development of gestational diabetes (158) and an increased risk of first trimester miscarriage in women (159). Vitamin D deficiency is linked with irregular glucose metabolism, potentially caused by compromised β cell function and insulin resistance (158), and vitamin D supplementation can improve insulin sensitivity (160). Thus, vitamin D may be a rate-limiting causal factor in the mechanism by which altered metabolic function underlies Treg cell deficiency.

Uterine NK cells play a key role in producing factors that support embryo implantation and the uterine vascular changes required to facilitate placental development and fetal growth (161, 162). Failure of an appropriate uNK cell response will lead to poor spiral artery remodeling and cause placental insufficiency, resulting in miscarriage, or later pregnancy complications (163) such as preeclampsia (164), depending on the severity of the defect. As well as Treg cells, there is evidence that hyperglycemia and type 2 diabetes can alter peripheral NK cells and cause loss of function (165, 166). Tissue from elective terminations shows that uNK cells from women with obesity have distinct gene expression profiles compared with uNK cells from nonobese women, including perturbations in growth factor signaling, which is linked with delayed maternal vascular remodeling in obese patients (167). Whether this is a reflection of direct effects of glucose on uNK cells, or whether these effects are indirectly mediated via modulatory effects of Treg cells on uNK cells, remains to be shown.

In addition to T cells and uNK cells, other leukocyte populations are impacted by metabolic factors. Both activated DCs and proinflammatory macrophages require aerobic glycolysis for energy production (168, 169), while oxidative phosphorylation is higher in M2-like macrophages and tolerogenic DCs (168, 170, 171). DCs are understood to play a key role in establishing an immune environment supportive of pregnancy (27), with changes in phenotype toward increased proinflammatory activation linked with recurrent miscarriage in women (172). Activation of the glycolysis pathway in these APCs leads to enhanced proinflammatory cytokine production, migration, and an increase in costimulatory molecules (173175). Therefore, elevated glucose associated with metabolic dysfunction, such as occurs in hyperinsulinemia and diabetes, is more likely to generate macrophages and DCs that produce proinflammatory T cell responses, particularity in an environment with limited Treg cells.

An understanding of the role of metabolic processes in governing T cell phenotypic fate provides an opportunity to target metabolic pathways to change T cell function and skew the balance toward a pregnancy supportive Treg cell–rich environment. One candidate target with therapeutic potential is mTOR, the key signaling molecule in T cell glycolysis that regulates proliferation and gain of proinflammatory Th1/Th17 function. Inhibition of mTORC1 by rapamycin dramatically increases FOXP3 expression and Treg cell differentiation in vitro, leading to cells with an enhanced suppressive capacity (176, 177). Rapamycin is a potent immunosuppressant that has been used clinically in organ transplantation medicine, where it is shown to boost Treg cell populations (178). This strong immune-suppressant activity is contraindicated in pregnancy where, similar to other broad immunosuppressant drugs such as prednisolone, it would be expected to compromise a healthy maternal immune response to pregnancy (179, 180). Observations of birth defects after rapamycin administration to pregnant animals indicates that alternative strategies will be required (181).

A likely safer option worthy of consideration is metformin. Metformin is the most commonly prescribed therapeutic for type 2 diabetes due to its capacity to control fasting blood glucose and glycosylated hemoglobin levels and improve insulin resistance (182). Metformin’s main action is to suppress gluconeogenesis in the liver, thus limiting glucose release from the liver into the blood (183). Metformin also activates AMPK, which inhibits mTORC1 and mTOR-driven glycolysis (184), reducing GLUT1 expression and glucose uptake by cells (120). It seems rational to expect that metformin may benefit insulin-resistant miscarriage patients by limiting glucose availability to the T cell pool, and reducing the molecular machinery required to drive glycolysis. This would be expected to reduce proinflammatory, glucose-dependent Th1 and Th17 T cell generation and promote a shift toward Treg cell production.

Although to date there are no clinical studies to specifically investigate the effects of metformin of Treg cells in pregnancy, several studies have examined the capacity of metformin to alter T cell responses in a nonpregnancy setting. Animal models show that metformin treatment changes the T cell phenotype balance with inhibition of Th1 and Th17 responses and promotion of Treg cell production (185188). In in vitro studies on human lymphocytes, metformin acted to limit CD4+ Tconv proliferation while decreasing Th1 and Th17 production and IFN type I responses and enhancing Treg cell generation (189, 190). When administered to patients, metformin treatment skews the T cell phenotype balance by increasing Treg cells and causing a decline in Th17 cells in peripheral blood (189). Metformin is currently used in women with gestational diabetes and is considered a safe drug during pregnancy with no evidence of teratogenic activity or effects on pregnancy complications such as miscarriage (191, 192). Studies to date show that metformin has promise in reducing the miscarriage rate in women with polycystic ovary syndrome (193, 194), who are at greater risk of miscarriage (195), are often insulin resistant (196), and have a greater likelihood of developing gestational diabetes (195). No studies in metformin-treated pregnant polycystic ovary syndrome patients have yet included analysis of T cell populations.

There are also nonpharmacological, low impact, and safe strategies that might have utility in targeting metabolic function to boost Treg cells in women intending to conceive. Weight loss (197), increased exercise (198, 199), and improved diet (200) are all able to boost Treg cell number while limiting inflammatory T cells, and they warrant evaluation in the reproductive setting. Vitamin D is another example of a readily accessible intervention where there is a biological rationale for evaluation in pregnancy. It has been shown that low vitamin D levels decrease the likelihood of conceiving and maintaining pregnancy (201), whereas higher levels of vitamin D exert an anti-inflammatory effect, accompanied by an increase in Treg cell abundance and function (202).

In this brief review, we argue that metabolic factors are likely to be an important contributing factor in the immune imbalance that is implicated causally in infertility and complications of pregnancy. In particular, there is a strong biological rationale for impaired glucose control contributing to inadequate numbers or impaired function of Treg cells in women who experience implantation failure, recurrent pregnancy loss, and preeclampsia. Altered glucose metabolism is emerging as an important factor (143, 197) associated with T cell imbalance in other clinical settings. Hyperglycemia and insulin resistance are increasingly common due to high-fat and high-sugar diets and are identified risk factors for infertility and recurrent miscarriage (58, 59, 203) and hypertensive disorders of pregnancy (204). We contend that there is a strong biological rationale for proposing that hyperglycemia and insulin resistance elicit their adverse effects on reproduction and pregnancy at least partly by inhibiting Treg cell generation and promoting proinflammatory Th1 and Th17 responses, as occurs in other clinical settings (142, 146). Emerging evidence is consistent with this mechanism, pointing to links between altered metabolic function and a skewed immune balance in women with fewer Treg cells, a reduced suppressive capacity, and/or an increase in proinflammatory Th17 cells and cytokines (40, 59, 154) (Fig. 1). Genetic causes (205) and several health conditions and lifestyle factors are linked with Treg cell insufficiency—including nutritional deficiency (200, 206), inflammatory and autoimmune conditions (207), and hormone status (79, 208)—so metabolic factors are unlikely to fully account for immune disorders in reproduction and pregnancy, and they have the potential to interact with other risk factors.

FIGURE 1.

Schematic illustration of postulated effect of metabolic status on adaptive immune response to pregnancy in women. We expect that in women with metabolic disorder associated with hyperglycemia and insulin resistance, elevated glucose availability will promote the mTOR-driven glycolysis pathway for ATP generation in T cells responding at conception, skewing their phenotype toward a Th1/Th17 cell–dominated outcome. This compares with the Treg cell–dominated outcome in women with healthy metabolism, as Treg cells preferentially employ fatty acid oxidation and oxidative phosphorylation for ATP generation (see text for details). A shift away from Treg cells and toward Teff cells may be exacerbated when other nutritional or metabolic factors are perturbed, such as vitamin D availability. An excessive Th1/Th17 bias is associated with infertility, recurrent miscarriage, and pregnancy disorders arising due to impaired placentation, while development of a robust placenta requires a strong Treg cell–dominated response. Created with BioRender.com.

FIGURE 1.

Schematic illustration of postulated effect of metabolic status on adaptive immune response to pregnancy in women. We expect that in women with metabolic disorder associated with hyperglycemia and insulin resistance, elevated glucose availability will promote the mTOR-driven glycolysis pathway for ATP generation in T cells responding at conception, skewing their phenotype toward a Th1/Th17 cell–dominated outcome. This compares with the Treg cell–dominated outcome in women with healthy metabolism, as Treg cells preferentially employ fatty acid oxidation and oxidative phosphorylation for ATP generation (see text for details). A shift away from Treg cells and toward Teff cells may be exacerbated when other nutritional or metabolic factors are perturbed, such as vitamin D availability. An excessive Th1/Th17 bias is associated with infertility, recurrent miscarriage, and pregnancy disorders arising due to impaired placentation, while development of a robust placenta requires a strong Treg cell–dominated response. Created with BioRender.com.

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Defining the relative contribution and causal relationships between metabolic dysfunction and immune imbalance in reproductive and pregnancy disorders is therefore a pressing research question. To evaluate this, it will be important to employ well-defined measures of metabolic status and high-quality T cell phenotyping analysis in patients. In the setting of infertility, there is general agreement that considerable heterogeneity in patient immune parameters exists, but robust immune phenotyping to classify patient subgroups is rarely applied. This has led to patients with unexplained infertility or pregnancy loss often taking unproven immunotherapies that may be unsuited to their clinical needs, or even harmful (179, 180, 209, 210). Novel treatments have little chance of success when there is high diversity in the nature of underlying immune dysfunction and the causes remain unclear. Developing the capability to incorporate metabolic status into informative diagnostic tests that classify women into subtypes of immune disorders will be a step toward developing tailored interventions. Better classification of patients using a robust immune–metabolic profiling approach will be essential to enabling well-designed clinical trials to assess metformin and other candidate therapies.

This work was supported by Department of Health/National Health and Medical Research Council Grant APP1198172.

Abbreviations used in this article:

     
  • DC

    dendritic cell

  •  
  • exTreg cell

    cell that undergoes transdifferentiation to effector Th1 or Th17 cell

  •  
  • GLUT1

    glucose transporter 1

  •  
  • HIF-1α

    hypoxia inducible factor 1α

  •  
  • mTOR

    mammalian target of rapamycin

  •  
  • pTreg

    peripheral Treg

  •  
  • Tconv

    conventional T

  •  
  • Teff

    effector T

  •  
  • Treg

    regulatory T

  •  
  • uNK

    uterine NK

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The authors have no financial conflicts of interest.