Role of Regulatory T cells and related cytokines-mediated immune tolerance

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Research progress on the role of regulatory T cells and related cytokines-mediated immune tolerance in allergic reactions induced by hydatid

Role of Regulatory T cells and related cytokines-mediated immune tolerance.  Echinococcosis is a common zoonotic disease on a global scale and has regional characteristics. Among them, cystic echinococcosis (CE) accounts for about 95% of the total, and a few are alveolar echinococcosis. (Alveolar echinococcosis, AE), has a huge impact on economic development and public health.

In recent years, studies have found that immune tolerance with regulatory T cells (Tregs) as the core plays an important role in allergic reactions caused by hydatid.

Through a variety of mechanisms, it successfully creates a suitable immune environment for tissue repair and limits tissue damage caused by inflammation. This article will focus on Tregs that play a key role in allergic reactions caused by hydatid, and the interaction between Tregs and related cytokines on the immune regulation of allergic reactions caused by hydatid.

1.   Tregs as the core immune tolerance

Tregs are a subtype of CD4+ T cells, which are of great significance for immune homeostasis and maintenance of self-tolerance. They were originally called inhibitory cells. Tregs can indirectly inhibit inflammation-induced tissue damage through various mechanisms such as anti-inflammatory and anti-apoptosis, and create a suitable immune microenvironment for tissue repair and regeneration. In addition, Tregs can play an inhibitory role in a variety of inflammatory environments. Immune tolerance with Tregs as the core is mainly composed of Tregs-related cytokines IL-10, transforming growth factor-β (transforming growth factor-β, TGF-β), and specific transcription factor protein forkhead box P3 (forkhead box P3, Foxp3). ) To jointly form and participate in maintaining the stability of the immune internal environment.

1.1 The role of IL-10 mediated immune tolerance in allergic reactions caused by hydatid

IL-10 can be produced by a variety of cell types including B cells, T cells, mast cells and dendritic cells. It is a proven anti-inflammatory and immunosuppressive factor. Tregs can produce IL-10 to suppress hypergenomic immune responses. Thereby protecting the host. IL‑10 can exert immunosuppressive effects through the following ways: ① IL‑10 can down-regulate the release of inflammatory factors from mononuclear macrophages and inhibit their antigen presentation, and induce the formation of immune tolerance. ② Inhibit Th1-mediated immune response by reducing the synthesis of IL-12. ③ Inhibit IL-23 on which Th17 cell immunity depends. Tregs secrete IL-10 in the process of echinococcal damage to tissues, and reduce the damage of infected tissues by inhibiting the secretion of TNF-α and the activity of neutrophils. They play an important role in the early immune pathological mechanism. In addition, after Echinococcus infection, IL-10 can exert an immunosuppressive effect by regulating the expression of programmed death 1 (PD-1). PD‑1 is a cell surface receptor, expressed on T cells and myeloid cells, and when combined with programmed death‑ligand 1, PD‑L1, it negatively regulates the immune response. PD‑L1 is constitutively expressed on dendritic cells, and temporarily expressed on T cells and monocytes after antigen activation. During hydatid infection, IL-10 secretion increases, which induces PD-1 expression and binds to PD-L1 to inhibit CD3-mediated T cell activity, including decreased cytokine secretion, decreased cell killing activity, and decreased proliferation ability. Therefore, prolonged exposure of T cells to IL-10 will cause T cell dysfunction, thereby forming immune tolerance.

After Echinococcus infection, the body quickly adjusts to maintain a stable immune environment. At this time, IL-10 in the body presents a high secretion state, which is conducive to the symbiosis of the human body and the parasite. Studies have shown that immune tolerance with Tregs as the core maintains an immunosuppressive state through the high secretion of IL-10. Ye et al. found that IL-4 and hydatid vesicle size are independent risk factors for anaphylactic shock caused by hydatid cysts during the perioperative period, and age and IL-10 are protective factors. When the IL-4 level is greater than 415.67 μg/L, there is a risk of anaphylactic shock caused by perioperative hydatid; when the diameter of the hydatid vesicle is greater than 7.8 cm, the patient is at a high risk of anaphylactic shock; when Every time the patient’s age increases by 1 year, the patient’s risk of anaphylactic shock due to hydatid is 0.962 times the original; for the same patient’s IL-10 before and after each increase of 1 ng/L, the risk of anaphylactic shock caused by hydatid The risk is only 0.677 times the original.

Therefore, when the patient’s age and the size of the hydatid vesicles are certain, the targeted regulation of IL-4 and IL-10 levels may become the research direction for reducing the incidence of anaphylactic shock caused by hydatid in the future. But as we know, the immunosuppressive state caused by the overexpression of IL-10 provides a good internal environment for tumor growth, lupus erythematosus and other diseases. If we increase the level of IL-10 before surgery, will it cause hydatid Is the disease progressing again? These issues need further study.

1.2 The role of TGF-β-mediated immune tolerance in allergic reactions caused by hydatid

TGF-β has a wide range of sources and can be synthesized by macrophages, lymphocytes, endothelial cells, etc., which can activate and maintain T cell activity, reduce cytotoxicity, balance various physiological states, and exert immune tolerance in chronic diseases. TGF-β alone can induce initial T cells to differentiate into Tregs. In the environment of infection and inflammation, TGF-β combined with the inflammatory factor IL-6 can induce initial CD4+ T cells to differentiate into Th17 cells, and TGF-β uses its downstream signals Pathways play an important role in cell proliferation. Studies have found that the expression levels of TGF-β and Smad proteins in the liver of mice infected with vesicular larvae have changed significantly, showing a gradual upward trend, suggesting that TGF-β and Smad proteins mediate the relationship between vesicular larvae and the host. Interaction. The main downstream effector protein of the TGF-β signaling pathway is the Smad protein family. TGF-β binds to TGF-β type II receptor to activate TGF-β type I receptor, which in turn activates Smad2 and Smad3 through phosphorylation. The phosphorylated Smad2 and Smad3 complex can bind to the Smad4 receptor and then translocate into the nucleus. In the nucleus, the Smad complex binds to the nuclear transcription factors Ror-γt and Foxp3 to regulate gene transcription. On the contrary, Smad7 can inhibit the formation of Smad complex and the phosphorylation of Smad2 and Smad3, thereby blocking signal transduction. Smad7 can also inhibit the interaction of Smad3 with TGF-β type I and TGF-β type II receptors. Therefore, Smad7 is a negative regulator in the TGF-β signaling pathway. In the early stage of hydatid infection, Smad7 is negatively regulated to inhibit the expression of Tregs and Th17. In the middle and late stages of Echinococcus infection, the number of Echinococcus gradually increases, and the TGF-β/Smad signaling pathway is activated without being inhibited by Smad7. TGF-β alone can induce T cells to differentiate into Tregs and promote the formation of immune tolerance. In the environment of infection and inflammation, TGF-β combined with inflammatory factor IL-6 can induce T cells to differentiate into Th17 cells through the TGF-β/Smad signaling pathway, causing the release of a large number of inflammatory factors, and ultimately leading to imbalance of immune tolerance.

In addition, studies have shown that patients with echinococcosis can affect the activities of natural killer (NK) cells and CD8+ T cells through TGF-β, thereby producing immune tolerance. Previous studies have found that in the peripheral blood mononuclear cells of AE patients, the proportion of NK cells and CD8+ T cells decreases and the cell activity is significantly reduced. NK cells and CD8+T cells are important immune regulatory cells in the body. One of their common ways of action is to perform immune surveillance and cell activation through the NK cell 2D (natural killer group 2D, NKG2D) receptor expressed on their surface. . In the early stage of hydatid infection, the patient’s peripheral blood and spleen showed high expression of TGF‑β, which inhibited the expression of NKG2D receptors on the surface of NK cells and CD8+ T cells, making it impossible to fully recognize the NKG2D ligand expressed by abnormal cells, resulting in NKG2D-dependent cytotoxicity is inhibited, thus reducing the killing activity of NK cells and CD8+ T cells, and ultimately leading to immune evasion of the host.

However, the immunosuppressive state produced by TGF-β plays a role in promoting tumor recurrence and other adverse conditions. The immunostaining results of CE patients indicated that there was a large amount of TGF-β at the edge of the hepatic hydatid cyst; another study confirmed that the expression of TGF-β gradually increased in the liver of BALB/c mice infected with AE. Whether this suggests that TGF‑β may have a potential role in promoting the growth of hydatid in the host, it still needs further verification.

1.3 The role of Foxp3-mediated immune tolerance in allergic reactions caused by hydatid

Tregs are involved in limiting tissue damage and inflammation related to innate and secondary immune responses, and play an important role in the maintenance of immune tolerance in patients with hydatid disease. Fontenot et al. have proved that Tregs are a specific cell lineage produced in the thymus many years ago, and their development depends on the expression of Foxp3. In mice, Foxp3 expression is limited to Tregs, so it is by far the best marker for Tregs subgroups. Foxp3+Tregs can inhibit the immune response by preventing the activation and proliferation of T cells and B cells, especially the initiation of the immune response. The genetic defect of Foxp3 can lead to a highly aggressive and fatal lymphoproliferative autoimmune disease that affects multiple organs, called immune dysregulation-polyendocrine disease-enteropathy-X-linked syndrome. Previous animal experiments have found that compared with the blank control group, the expression of Foxp3 in the echinococcosis model group was significantly increased, and the proportion of CD4+CD25+ Foxp3+ cells increased. After the sensitization was attacked with the crude cystic fluid of Echinococcus granulosus, the sensitized group was smaller Mouse Foxp3 expression decreased significantly. It can be concluded that the reduction of Foxp3 expression can weaken the immunosuppressive function of Tregs to a large extent, cause the imbalance of Tregs-related immune tolerance, and ultimately lead to allergic reactions. It is currently believed that after allergic reactions caused by hydatid cysts, some cytokines (such as TNF and IL-6) and over-activated phosphatidylinositol 3-kinase/protein kinase B signals down-regulate the expression of Foxp3, resulting in Tregs as the core The immune tolerance is destroyed.

However, in recent years, studies have found that when Foxp3+Tregs are exposed to an inflammatory environment, they can be transformed into pathogenic Th17 cells. This has raised concerns about Tregs as therapeutic targets in the future. The instability of Foxp3+ expression has gradually been reduced. attention. Cortez et al. stained the endogenous Foxp3 protein and sorted the cells expressing Foxp3 according to the level of expression. They found that the transcriptional and post-transcriptional levels of the intracellular regulator Usp22 are consistent with the expression of Foxp3, and proposed Usp22 It is a positive regulator of Foxp3 expression and a necessary regulator for histone deubiquitination. It affects the expression of Foxp3 by regulating transcriptional activity. Therefore, using Usp22 as a target to affect the expression of Foxp3 can stabilize the function of Tregs, and may become a new method for the treatment of hydatid disease.

2. The effect of Tregs changes on allergic reactions caused by hydatid

2.1 　Th17/Tregs imbalance causes Tregs to decrease

In patients with echinococcosis, especially those with recurrent echinococcosis, the proportion of Tregs in the body increases, and the immune tolerance with Tregs as the core gradually takes the lead. This is an important factor leading to the long-term symbiosis of the human body and the parasite. However, studies have shown that the proportion of Tregs is significantly reduced under inflammatory conditions, mainly due to the instability of Tregs in the inflammatory environment. Under inflammatory conditions, Foxp3+Tregs can transdifferentiate into pathogenic Th17 cells, and TGF‑β combined with inflammatory factor IL‑6 can induce T cells to differentiate into Th17 cells through the TGF‑β/Smad signaling pathway. Th17 and Tregs act oppositely and restrict each other. When one side increases, the other side passively decreases. The cytokine IL-17 mainly secreted by Th17 cells often acts as a pro-inflammatory factor. It not only protects the host by eliminating hydatid through inflammation, but also causes autoimmune pathological damage in the body, leading to a large number of inflammatory cell infiltration and liver Cell fibrosis and necrosis. When Th17/Tregs is imbalanced and biased towards Th17, immune tolerance is broken and inflammatory factors are released in large quantities, which eventually leads to the occurrence of allergic reactions caused by hydatid. Previous experiments have found that the levels of IL-10 and TGF-β secreted by Tregs in mice in the hydatid sensitized group decreased, while IL-17 secreted by Th17 increased significantly. Therefore, it is proposed that the up-regulation of Th17 and the down-regulation of Tregs are the key link in causing allergic reactions caused by hydatid.

In clinical practice, immunotherapy targeting Tregs has been regarded as a new strategy for cancer treatment in recent years. Studies have confirmed that a large number of Tregs undergo apoptosis in the state of cancer, but down-regulation of Tregs expression does not eliminate the immunosuppressive state of tumor patients. The reason is that apoptotic Tregs still have immunosuppressive effects. The difference is that apoptotic Tregs no longer exert immunosuppressive effects by secreting IL-10, TGF-β and other related cytokines, but convert ATP into adenosine and then exert immunosuppressive effects through the adenosine A2A receptor pathway. Therefore, down-regulation of Tregs is an important factor in immune tolerance imbalance, but it is not the only cause. Then, in the special immune state of allergic reactions caused by hydatid, will the down-regulation of Tregs make the patient’s immune suppression completely disappear? Can apoptotic Tregs also exert immunosuppressive effects through other ways? Still need to continue in-depth research.

2.2 The mechanism and clinical application of Tregs up-regulation

After the body is infected with hydatid, it can up-regulate the level of Tregs through the TGF-β/Smad signaling pathway. In the early stage of infection, the expression of Smad7 increases, blocking the translocation of Smad2/3 complex to the nucleus and TGF-β signal transduction. The mRNA level of Th17 cell-specific transcription factor RoR‑γt and Tregs-specific transcription factor Foxp3 was low. In the mid-stage of infection, the expression levels of TGF-β, TGF-β type II receptor/TGF-β type I receptor and Smad2/3 increase, while the expression level of Smad7 decreases, which induces the activation of the TGF-β/Smad signaling pathway. At the same time, the expression levels of RoR-γt and Foxp3 increased significantly, and the number of Th17 cells and Tregs increased significantly. The levels of related cytokines IL-17, TGF-β and IL-10 also increased significantly. In the later stage of infection, the TGF-β/Smad signaling pathway is still active, but the transformation of Th17 cells is reduced due to the decrease of IL-17 and IL-6 levels. Foxp3, Tregs, TGF‑β and IL‑10 are still at high levels, and the overall bias is towards Tregs, which contributes to the formation of immune tolerance.

Allergic reactions caused by echinococcosis are common and fatal, so it is necessary to prevent allergic reactions caused by echinococcosis in advance. Studies have shown that during the process of parasite infection, the expression of Tregs and its related factors increase, which helps maintain immune tolerance and reduces the incidence of allergic reactions caused by hydatid. In clinical case reports, pretreatment with a small dose of dexamethasone before the excision of hydatid cysts to prevent allergic reactions caused by hydatid cyst fluid overflow is a routine treatment. Zhang et al. studied the mechanism of dexamethasone in preventing allergic reactions to hydatid cysts. Through the use of dexamethasone to pretreat C57BL/6 mice and then sensitize them, they found that the hormone pretreatment group was compared with the simple sensitization group. The incidence of severe allergic reactions was 12.5% ​​and 37.5%, respectively. According to immunological analysis, the serum levels of IgE, IgG and IgG1 in the dexamethasone pretreatment group and the histamine expression in lung tissues were lower than those in the simple sensitization group, and the difference was statistical Learn meaning.

In addition, the study found that the changes of CD4+CD25+Foxp3+/CD4+, serum IL-10 and TGF-β levels were the same, and they all increased in the dexamethasone pretreatment group, while the pure sensitization group showed the opposite. It shows that dexamethasone may play an anti-allergic effect by up-regulating the ratio of CD4+CD25+Foxp3+Treg cells. Dexamethasone prevents allergic reactions caused by hydatid cysts by affecting the function of Tregs, up-regulating the levels of IL-10 and TGF-β, and inhibiting the levels of Th2 cytokines IL-13 and IgE to maintain immune balance.

3.  Future Outlook

Through continuous elucidation of the role of Tregs and their related cytokines IL-10, TGF‑β and the specific transcription factor Foxp3 in allergic reactions caused by hydatid, we found that the immune tolerance mediated by Tregs and related cytokines is in It plays an important role in maintaining the stability of the immune environment.

This imbalance of immune tolerance is an important factor leading to allergic reactions caused by hydatid. Therefore, maintaining the immune tolerance mediated by Tregs and related cytokines should be used as a therapeutic target to prevent allergic reactions caused by hydatid.

However, there is a single way to prevent allergic reactions caused by hydatid. In addition to the known pretreatment with dexamethasone, other methods need to be further studied. Future research can provide deeper research directions on the specific mechanisms and prevention strategies of allergic reactions caused by hydatid cysts by regulating the immune tolerance mediated by Tregs and related cytokines.

Role of Regulatory T cells and related cytokines-mediated immune tolerance

Role of Regulatory T cells and related cytokines-mediated immune tolerance

Role of Regulatory T cells and related cytokines-mediated immune tolerance

(source:internet, reference only)

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