According to the modern tenets of reproductive immunology, pregnancy can be regarded as a triumphant outcome of a natural allograft. The fetus successfully evades rejection owing to the presence of the immune barricade of the placenta, immunosuppressive cells, and immunomodulators within the maternal environment. Thus, a successful pregnancy depends on the balance of immunity between the fetus and the mother. In other words, maternal-fetal tolerance is the key to a successful pregnancy. Furthermore, the interaction between the maternal and fetal systems, as well as the impact of fetal cells circulating within the maternal bloodstream and inducing an inflammatory response, warrants consideration (1). Loss of maternal immune tolerance, causing immune rejection, may lead to pregnancy pathology such as pregnancy-induced hypertension (PIH) (2), abortion, and other conditions (3). PIH is a pregnancy-specific disorder characterized by the onset of hypertension (systolic blood pressure ≥140 mmHg or diastolic blood pressure ≥90 mmHg) after 20 weeks of gestation in the absence of proteinuria or other organ dysfunction. The severity of PIH is classified into three stages: mild, moderate, and severe. PIH is a serious condition that can lead to significant maternal and fetal morbidity and mortality. The risks associated with PIH include placental abruption, fetal growth restriction (FGR), preterm birth, and maternal organ damage, such as liver and kidney dysfunction (4). If left untreated, PIH can progress to preeclampsia (PE) or eclampsia, which are even more severe conditions that can be life-threatening for both mother and fetus (5). Adopting an immunological perspective can be instrumental in uncovering and comprehending the etiology and pathogenesis of PIH, thereby providing valuable insights for the prevention, diagnosis, treatment, and care of PIH.

The most recognized model of PIH is poor placentation due to abnormal spiral artery formation, while immune modulation of trophoblast invasion is thought to play an important role in the pathogenesis of PIH (6). The maternal immune response to fetal alloantigens is dynamic and ideally shifts between immune suppression and response during placentation, with pregnancy gestation, and then birth (7). In a normal pregnancy, the maternal immune system undergoes changes to accommodate the fetus and prevent it from being recognized as foreign (8). This includes the production of certain immune cells and molecules that suppress the immune response and promote tolerance to the fetus. The rejection reaction, on the other hand, occurs when the immune system recognizes the fetus as foreign and launches an attack against it. However, in pregnant women with PIH, there is a decrease in the protective response and an increase in the rejection reaction (9). This means that the mother’s immune system is more likely to perceive the fetus as a threat and attack it, potentially leading to complications. Chemokine gene silencing in decidual stromal cells restricts the entry of T cells into the maternal-fetal interface. Effector T cells cannot accumulate in the decidua, the special stromal tissue that surrounds the fetus and placenta (10). Moreover, the regulation and recruitment of inducible regulatory T cells by trophoblast cells occur during early pregnancy (11). A large number of studies have shown that the T helper (Th) cells subgroup and their secreted cytokines play a core regulatory role in pregnancy immunity and are closely related to the occurrence of PIH (7, 9, 12, 13).Therefore, even in the presence of a small number of T cells, the effects of T cells themselves and their secreted cytokines are noteworthy.

T helper subsets primarily achieve their physiological functions through the release of cytokines. These cytokines have broad biological effects, including regulating the activation and proliferation of immune cells, regulating inflammatory responses, and affecting biological processes such as cell proliferation, differentiation, and apoptosis. In this article, we mainly focus on the effects of cytokines produced by T helper subsets on the placental trophoblast and other immune cells, and the association of these effects with the development of PIH ( Figure 1 ). In this perspective, we will summarize the role of T helper subsets (TH1/2/17 and Treg) in PIH and explore the role of relevant cytokines in the pathogenesis of PIH.

The Th cell-mediated adaptive immune response represents a critical component in the intricate mechanism of maternal-fetal immune tolerance. Upon encountering a diverse array of cytokine stimuli, the Th0 cells, which originate from initial CD4+ T cells, undergo differentiation into distinct subsets including Th1, Th2, Th17, and Treg cells, each of which assumes discrete biological functions (13). Th1 cells mainly secrete IFN-γ, TNF-α, and other cytokines, which have cytotoxic effects, and can inhibit the invasion of trophoblasts and induce their apoptosis. (53) Th1 cells can also inhibit embryo implantation by enhancing the vitality of decidual macrophages, which is not conducive to the maintenance of pregnancy (54). In contrast to Th1 cells, Th2 cells possess the capacity to produce IL-4 cytokines, which act to promote trophoblast cell proliferation and invasion, enhance uterine receptivity, and confer immune-nutritive and protective benefits to the fetus (55, 56).

Th17 cells mainly mediate inflammatory diseases and autoimmune diseases, and the cytokine IL-17 secreted by Th17 can promote the invasion of extracellular villus trophoblast cells and inhibit their apoptosis (57). Treg cells promote CD4+CD25-T differentiation to CD4+CD25 + Treg by secreting inhibitory cytokines such as TGF-β, showing the advantage of Treg cells at the mother-fetal interface and indirectly playing the role of immunomodulator (58).

Therefore, normal physiological pregnancy mainly presents a Th2-type immune advantage and the Treg cell amplification phenomenon. Th1/Th2 and Th17/Treg balance is an essential condition for maintaining normal pregnancy. On the other hand, Th1/Th2 and Th17/Treg balance play a role in maintaining maternal-fetal immune tolerance (14). Research has reported that the number and function of Th cells and the ratio of Th1/Th2 in patients with PE were significantly decreased (59). Therefore, paying attention to the changes of Th1/Th2 in PIH that may exist before the occurrence of PE is of great significance for understanding the development mechanism of PIH during pregnancy.

Cytokines play a complex role in the pathophysiology of PIH and PE (60). The direct effects of cytokines on myocardiocytes to suppress contractility can also have negative consequences for maternal and fetal cardiovascular function (61). The endothelial injury caused by PE can lead to peripheral edema and other complications (62). Overall, the effects of cytokines on the maternal-fetal interface and cardiovascular system in PE are complex and require further research to fully understand. In this article, we will discuss selected cytokines produced by T helper subsets. We will focus on their effects on the immune environment, inflammatory processes, and trophoblast invasion.

Cytokines secreted by Th2, such as IL-4, IL-6, and IL-10, can inhibit the Th1 immune response and the activation of NK cells to protect the fetus (74). These cytokines mainly participate in B cell proliferation and maturation, which can increase the antibody-mediated immune response.

Th17 cells secrete a number of pro-inflammatory cytokines, including IL-17, IL-21, and IL-22, which have been found to be elevated in the circulation of women with PIH (80). These cytokines may contribute to the development of hypertension and endothelial dysfunction, which are key features of PIH.

IL-17, in particular, has been implicated in the pathogenesis of PIH (81). It induces the production of other pro-inflammatory cytokines and chemokines, such as IL-6 and TNF-α (45), which contribute to the development of hypertension and endothelial dysfunction. IL-17 also stimulates the production of reactive oxygen species (ROS) (46), which can lead to oxidative stress and endothelial damage. Additionally, IL-17 promotes the infiltration of neutrophils and macrophages into the placenta (47), which can further contribute to inflammation and tissue damage.

IL-21 and IL-22 have also been shown to be elevated in women with PIH. IL-21 promotes the differentiation and activation of Th17 cells, and can enhance the production of IL-17 and other pro-inflammatory cytokines (48). IL-22, on the other hand, has been implicated in the regulation of angiogenesis and VEGF signaling (49), which are important processes in the development of placental vascularization and function.

Taken together, the cytokines produced by Th17 cells are important contributors to the pathogenesis of PIH, promoting inflammation, oxidative stress, endothelial dysfunction, and vascular damage. Targeting these cytokines may provide a potential therapeutic strategy for the prevention and treatment of PIH.

Tregs are a subset of T cells that regulate immune responses and maintain tolerance to self-antigens. They produce cytokines such as IL-10 and TGF-β, which have anti-inflammatory and immunosuppressive effects. Several studies have reported lower levels of Tregs in women with PIH compared to normotensive pregnant women (82). This suggests that a deficiency in Tregs may contribute to the development of PIH. In addition, decreased production of IL-10 and TGF-β has been observed in women with PIH (83), further supporting the role of Tregs in the development of PIH. Moreover, it has been shown that administration of TGF-β can ameliorate PIH in a rat animal models study (50). This suggests that Tregs and their cytokines may have therapeutic potential for the treatment of PIH.

In brief, the etiology and pathogenesis of PIH in immunological investigations are posited to arise from the dysregulation of maternal-fetal immune homeostasis or immune tolerance, characterized by diminished Th2-mediated immunosuppression and/or heightened Th1-mediated cellular immune activation Table 1 .

PIH represents a prevalent condition in obstetrics and has been a subject of intense research. Numerous etiological and pathogenic mechanisms have been proposed, including the immune response theory, oxidative stress theory, capillary endothelial injury theory, and others. However, thus far, none of these theories have fully accounted for the multifaceted pathophysiology of PIH. Here, we briefly summarized the close relationship between Th1 cells, Th2 cells, and the released cytokines and PIH from the perspective of immunology, and discussed the possible occurrence and development mechanism. Overall, although PIH is caused by many factors, the immune factor plays a pivotal role. Therefore, it may be more effective to prevent, diagnose, treat, and care for PIH by focusing on immunological indicators.

The pathogenesis of PIH is still unclear, which makes clinical diagnosis and treatment difficult. The current diagnosis of PIH and PE mainly focuses on hypertension, proteinuria, serum biochemical abnormalities, and fetal growth. It can be seen from this review that the pathogenesis of PIH may be related to immune factors to a certain extent. In recent years, researchers have suggested that the serum levels of inflammatory factors associated with the pathogenesis of PIH and PE may become part of the diagnostic criteria. For example, a study by Li et al. found that serum levels of IL-6 and TNF-α were significantly higher in women with early-onset PIH compared to normotensive pregnant women (29). They proposed that serum levels of IL-6 and TNF-α could be used as potential biomarkers for early diagnosis of PIH.

Significantly, immune modulation is anticipated to emerge as a novel therapeutic target for PIH and PE in clinical management and holds considerable promise in ameliorating maternal mortality. This approach aims to modulate the immune response by regulating key immune pathways and cytokines, such as interleukin-6 (IL-6) and interleukin-10 (IL-10), and may improve outcomes for women with PIH and PE. Immune modulation strategies for the treatment of PIH and PE include the use of immunomodulatory agents and the development of novel targeted therapies. For example, Tinsley et al. (84) used a PIH rat model of deoxycorticosterone acetate (DOCA)/salt-low renin, which exhibits features of hypertension, proteinuria, endothelial dysfunction, and intrauterine growth restriction (IUGR). Furthermore, suppression of the immune system with either azathioprine (Aza) or mycophenolate mofetil (MMF) during the second half of pregnancy significantly reduced hypertension, proteinuria, and endothelial dysfunction, as well as increased the proinflammatory Th1 cytokine profile in rats treated with DOCA/salt, which alleviated the development of PIH. Medications that target the immune system, such as anti-inflammatory drugs or targeted immunotherapy agents, may be beneficial for PIH patients with an overactive immune system. However, medication interventions should be tailored to the individual patient based on their immunological profile and other medical conditions.

QZ, YW, and DZ wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.