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Regulatory T cells (Tregs) in liver fibrosis

Regulatory T cells (Tregs) in liver fibrosis www.nature.com/cddiscovery REVIEW ARTICLE OPEN Regulatory T cells (Tregs) in liver fibrosis ✉ ✉ 1,7 2,7 2,7 1 1 3 4,5,6 1,6 Ke-jia Wu , Qu-fei Qian , Jin-ren Zhou , Dong-lin Sun , Yun-fei Duan , Xi Zhu , Kurt Sartorius and Yun-jie Lu © The Author(s) 2023 The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate fibrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates fibrogenesis in response to the imbalance between ECM accumulation and fibrosis resolution. Liver disease that induces fibrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver fibrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2–dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver fibrogenesis which includes its promotion of immunosuppression, as well as its activation of fibrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver fibrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease. Cell Death Discovery (2023) 9:53 ; https://doi.org/10.1038/s41420-023-01347-8 INTRODUCTION immune cells that respond to chronic inflammation, tissue Liver fibrosis is generally considered to be the consequence of regeneration, ECM remodelling and fibrogenesis [6]. A hallmark ongoing chronic liver injury and a leading pathogenic factor of event of liver fibrosis is the activation and expression of HSCs morbidity and mortality in chronic viral hepatitis and obesity- which are regulated by several immune mediators, including Th9, related fatty liver disease worldwide [1]. Non-resolving liver Th22, Tregs, innate lymphoid cells (ILCs), mucosal-associated fibrogenesis, stimulated by a wide range of risk factors, induces invariant T cells (MAIT), and γδT cells, along with their associated the activation of quiescent hepatic stellate cells (HSCs) into cytokines [7]. In early-stage fibrosis that is resolved, the immune myofibroblasts that are the primary extracellular matrix (ECM)-cell response contributes to terminating HSC activation and fibrous type that promotes fibrous protein deposition and scarring [2]. protein expression, however, in the case of ongoing liver disease, The severity and outcome of fibrogenesis in liver disease can be the complicated interplay of these immune mediators often triggered by a wide range of risk factors including viral infection, promotes liver fibrosis. A key change in the adaptive immune toxins, and a range of non-communicable diseases that contribute response is the mobilization of regulatory T(Tregs) cells that play to a build-up of fatty tissue in the liver. Chronic hepatitis infection, an immunosuppressive role to promote immune self-tolerance for instance, promotes liver fibrosis that can translate into cirrhosis and homoeostasis. The Treg family includes natural Tregs(nTregs) and the onset of neoplasms (Chronic hepatitis→ liver fibrosis→ that express the nuclear transcription factor FoxP3, as well as cell liver cirrhosis→ Liver Neoplasms) [3]. In patients suffering from surface proteins CTLA-4 and CD25 and induced Tregs(iTregs) [8, 9]. chronic liver injury, progression to the end stage usually takes 20 An increase of Tregs in fibroproliferative sites influences the to 40 years depending on whether both environmental and subsequent balance between tissue inhibitors of metalloproteina- genetic elements are causal factors [1]. Early-stage fibrosis is more se(TIMP) and matrix metalloproteinase(MMP) and Kupffer cell (KC) easily resolved while advanced liver fibrosis can result in a range expression to promote ECM remodelling and fibrogenesis [10]. In of severe symptoms, such as cirrhosis, liver failure, and portal addition, the Treg/TH17 ratio plays a key role in the process of hypertension [4], When fibrogenesis progresses to decompen- intrahepatic immune regulation and the dysregulation of this ratio sated cirrhosis, the survival period of patients is significantly is a key characteristic of the progression of liver fibrosis [7]. shortened, and therapeutic options are eventually limited to liver Restoring Treg/Th17 balance can effectively immunize against transplantation [5]. various intracorporal and extracorporeal pathogens, as well as Fibrogenesis as a result of liver injury involves a complex prevent excessive autoimmune self-harm [11]. However, further interactome that includes the interaction of various types of research on Tregs and the Treg/Th17 role in the fibrogenesis 1 2 Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China. The First Affiliated Hospital of Nanjing 3 4 Medical University, Nanjing 210000, China. Department of infectious diseases, the First Peoples’ Hospital of Kunshan, 215300 Kunshan, China. Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa. School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban, South 6 7 Africa. Africa Hepatopancreatobiliary Cancer Consortium, Mayo Clinic, Jacksonville, USA. These authors contributed equally: Ke-jia Wu, Qu-fei Qian, Jin-ren Zhou. email: sin0112@163.com; lyj0001@suda.edu.cn Received: 23 November 2022 Revised: 24 January 2023 Accepted: 27 January 2023 Official journal of CDDpress 1234567890();,: K. Wu et al. Fig. 1 The role of Treg in promoting fibrosis. Liver fibrosis is primarily induced by HSCs that promote TGF-β based production of myofibroblasts that stimulate ECM-driven fibrogenesis. Tregs can also activate HSCs to promote fibrosis through the TGF-β pathway. Treg can + + + induce HSCs via the expression of IL-8. Treg cells with CD4 CD25 Foxp3 can be selectively expanded by HSCs in an IL-2–dependent pattern. Tregs can directly suppress NK cells from degranulating in the role of IL-8, TGF-β1, and CTLA-4 signalling pathways. Footnote: hepatic stellate cells (HSCs), transforming growth factor-β (TGF-β), extracellular matrix (ECM), matrix metalloproteinase (MMP), regulatory cells (Treg), kupffer call (KC), interleukin-2 (IL-2), natural killer cell (NK cell), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). interactome is needed to promote potential diagnostic and surface: CD25, CTLA-4, PD-L1, GITR, and HLA-DR [20, 21]. The therapeutic options. This review outlines the current under- expression and functions have significant differences between standing of the role/s of Tregs on liver fibrosis. First, we review the naïve and activated Tregs, suggesting another dimension that the known pathways of Tregs that promote fibrogenesis and second tissue Tregs express higher levels of activation markers compared the role of Tregs and their related cytokines that suppress to blood. For example, activated effector Tregs (CD45RA- fibrogenesis. Thirdly, we outline the potential effects of the Treg/ FOXP3high) express high levels of HLA-DR compared to naïve Th17 balance and their related cytokines on fibrogenesis and Tregs (CD45RA FOXP3low) [22, 23] and activated Treg cells play a finally, we illustrate the complex Treg interactome and discuss the major role in fibrogenesis. Although Treg cells only account for potential for Treg therapy to be exploited for the treatment of 5%-10% of the total CD4 T lymphocytes in peripheral blood [24], fibrosis of the liver. their contribution to maintaining immune tolerance and homo- eostasis cannot be ignored. BACKGROUND AND ROLE OF TREGS Treg cells were first discovered by GERSHON et al. [12] in the THE PRO-FIBROSIS FUNCTION OF TREG 1970s and were referred to as “suppressor cells” because of their Activated Tregs are essential during the healing period to end role in immune regulation. A later study in 1995 showed that inflammation and promote wound healing [25] and yet recent CD25 expression was a hallmark of these suppressor cells that evidence indicates that a large number of Tregs are distributed in were labelled for the first time as Tregs [13]. This study also the fibrotic microenvironment in HCC patients. Interestingly, a + + demonstrated that the in vivo transfer of CD4 CD25 Treg- reduction in Tregs promoted the regression of fibrosis [26] deficient T cells triggered autoimmune disease in a mouse model. illustrating that Tregs play a prominent role in promoting fibrosis + + + + + Conversely, autoimmune effects were retarded when CD4 CD25 [Fig. 1]. A report showed Treg cells with CD4 CD25 Foxp3 were cells were introduced. The prevailing view is that there are two selectively increased by HSCs in an interleukin-2–dependent main sub-types of Tregs determined by cellular origin, namely, pattern [27] explaining the abundance of Tregs in fibrotic tissue natural Tregs(nTregs), which are differentiated in the thymus from [Fig. 1]. MMPs, the main enzyme involved in ECM degradation [28] progenitor cells derived from bone marrow, and inducible Tregs are produced primarily by KCs [29], however, even a low ratio of (iTregs), which are differentiated from peripheral naïve T cells to Tregs can repress KC expression of MMPs. Treg cells regulate the respond to infectious challenges. Except for nTregs and iTregs, balance of MMP/TIMP through KCs, thereby inhibiting the various studies have identified other T cells with regulatory resolution of fibrosis [4] [Fig. 1]. properties, including T helper (Th)-like Treg subsets, CD8 Tregs, Experiments have shown that Tregs may inhibit KCs from Tr1 cells, and Th3 cells [14–17]. In addition, many researchers have secreting MMP in vivo through the TGF-β pathway [30] [Fig. 1]. A subdivided Treg cells into different subsets in different diseases parallel increase in collagen type I deposition and TGF-β1 Tre g according to the different expression of Treg cell surface cells was observed in lymphoid tissues of the simian immunode- molecules, such as “Treg B” that shows a higher expression of ficiency virus (SIV) -infected rhesus monkeys 7 days after inocula- hi lo + CD95, CCR4, and CD45RO within FOXP3 , CD127 Tregs in tion [31]. These results indicate that TGF-β1 Treg cells have a aplastic anaemia [18]. Transcription factor forkhead box protein 3 dichotomous response to immune activation; on the one hand, (FoxP3) is the most characteristic marker of Treg cells and plays an they can inhibit viral immune response while on the other hand, important role in Treg development and immune regulation. Tregs they can induce collagen deposition in lymphoid tissues, resulting mainly secrete IL-10, TGF-β, IL-35, and other cytokines, which in organ fibrosis. enable the body to obtain immune tolerance by inhibiting the HSCs which are spread over the Disse space are generally differentiation and proliferation of NKT cells, macrophages, B cells, considered to be the hallmark cells of fibrosis and the major and so on [19]. Treg cells express the following molecules on their source of myofibroblasts and activation of HSCs is the initiating Cell Death Discovery (2023) 9:53 K. Wu et al. Fig. 2 The role of Treg in inhibiting fibrosis. IL-2 as well as its complexes accelerate Tregs expressing CD39 in the liver, thereby inhibiting the multiplication of CD8 T cells and its function of generating TNF-α and osteopontin, which can reduce biliary fibrosis. Tregs can regulate the high high pro-fibrotic roles of Th2 cells and Ly-6C CCR2 inflammatory monocytes/macrophages that secrete IL-4 and TGF-β respectively, interestingly, IL-10 secreted by Tregs may regulate them. Tregs can regulate the TGF-β-IDO signalling pathway to enhance the function of hAMSC that repress liver fibrosis. Tregs promoting the expression of amphiregulin can inhibit the development of fibrosis by promoting the proliferation of hepatocytes. In CCL4-induced liver fibrosis, rapamycin has an effective protective effect on the liver. Rapamycin significantly + + increased the functional activity of CD4 CD25 Tregs and enhanced the inhibitory ability of Tregs on HSCs activation. Tregs can repress MCP- 1 which plays an important role in liver fibrosis by activating HSC production. Tregs can directly repress CD4 T cell expression that reduces IFN-γ activated HSCs. Tregs also directly promote amphiregulin to repress liver fibrosis. Footnote: interleukin (IL), regulatory cells (Treg), transforming growth factor-α (TGF-α), T helper cell (Th), indoleamine 2,3-dioxygenase (IDO), human amniotic mesenchymal stromal cell (hAMSC), carbon tetrachloride(CCL4), hepatic stellate cells (HSCs), monocyte chemotactic protein-1 (MCP-1), Interferon-γ (IFN-γ). event of hepatic fibrosis. HSCs themselves can regulate the and α-SMA regions), it has also been demonstrated that deletion development of fibrosis. On the one hand, in the presence of of IL-8 can inhibit the activation of HSCs, however, the immune inflammatory stimuli, resting HSCs are often activated and regulatory function of Treg cells was not affected, illustrating that converted into myofibroblast-like cells and generate large IL-8 Tregs can promote fibrosis [39] [Fig. 1]. amounts of ECM and cytokines [Fig. 1]. On the other hand, In summary, the complex Treg interactome reveals that Treg activated HSCs can secrete MMPs to degrade ECM [32] [Fig. 1]. It expression can secrete IL-8 to activate HSCs that, in turn, can can be said that HSCs largely determine the promotion or secrete IL-2 to induce Treg expression. Tregs can secrete TGF- β to regression of liver fibrosis. In addition, TGF-β1 secreted by repress KC expression of MMPs that degrade ECM accumulation to macrophages is the strongest known activator of HSCs [33]. promote fibrogenesis and Treg-secreted TGF- β promotes HSC- Meanwhile, the two most important cytokines secreted by Tregs derived myofibroblasts. Tregs also promote fibrogenesis by are TGF-β and IL-10 [34] and Tregs can activate HSCs to promote secreting Il-8, TGF- β and CTLA-4 to repress NK repression of fibrosis through the TGF-β pathway [Fig. 1]. HSC activation. Tregs thus interact with multiple cell types and Of note, HBV which is one of the main pathogenic factors activate a range of cell–cell interactions with HSCs, NKs and KCs to leading to liver fibrosis can induce the generation of immuno- promote fibrogenesis (Fig. 1). suppressive cells, such as Tregs, MDSCs, and NK-REG cells, through the immunosuppressive cascade, undue induction can lead to adverse outcomes, such as liver fibrosis and even HCC [35]. HBV- THE ANTI-FIBROSIS FUNCTION OF TREG induced Tregs may suppress the antifibrotic function of NK cells It is interesting to note that TGF-β generated by Tregs in HCV is and directly suppress NK cells from degranulating in the role of IL- inversely associated with the regression of liver inflammation and 8, TGF-β1, and CTLA-4 signalling pathways [Fig. 1]. Tregs can also fibrosis, even though cytokine TGF-β is a well-established pro- have an indirect protective effect on HSCs from NK cell’s attack on fibrotic element, suggesting that TGF-β also has antifibrotic account of suppressing the expression of MICA/B on HSCs through properties [40]. According to the observation, the large number TGF-β1 and IL-8 [36]. Tregs can inhibit NK cells and M1 KCs from of highly differentiated and activated Tregs distributed to participating in the immune regulation of liver fibrosis, and its infiltrating chronic HCV-infected livers can lead to a limitation of immunosuppressive regulation contributes to the development of the degree of fibrosis. [41] Tregs in the peripheral blood of HCV chronic inflammation, thus maintaining liver fibrosis [37]. There- patients can suppress the proliferation of HCV-specific T cells and fore, by cutting off the pathway of Treg action on NK cells and IFN-γ [42]. In addition, the depletion of Tregs restored the restoring antiviral T-cell responses, the development of inflamma- secretion of IFN-γ by CD4 T cells [43] [Fig. 2]. This indicates that tion and injury can be limited, and HSCs, as a crucial element of Tregs in an HCV-induced environment are pivotal in the limitation liver fibrosis, can be reduced, thereby limiting the development of of collateral injury and homoeostasis maintenance by inhibiting liver fibrosis. an intemperate immune response. In addition, according to experimental observation, Treg cells Treg cells can guard against HIV-1-induced liver fibrosis, and the have been shown to proliferate during chronic HCV infection [38] mechanism may be related to the activation of HSCs, liver injury, and are enriched in liver fibrosis tissue to protect HSCs from NK and hepatitis [44]. In this regard, one study investigating HIV-1- cell attack [36]. Interestingly, an abundance of T cells with induced liver fibrosis deleted Treg cells with denileukin diftitox. By + + + IL-8 CD4 Foxp3 are found in HCV liver tissue (mainly in fibrotic measuring various plasma indicators, Only HIV-1+ denileukin Cell Death Discovery (2023) 9:53 K. Wu et al. diftitox mice in infection showed a significant increase in ALT value for the treatment of liver cirrhosis [58] [Fig. 2]. It was also levels after 20 days. Similarly, serum hyaluronic acid levels, also a proved that mesenchymal stem cells(MSCs) as well as MSC- sign of liver injury and fibrosis, were only elevated in infected HIV- conditioned medium (MSC-CM) both inhibited necroinflammatory 1+ denileukin diftitox mice after 20 days. Therefore, HIV-1 and fibrogenesis in a chronic liver injury model, however, the infection together with Tregs depletion causes liver inflammation second therapy had a better effect. In this regard, the activation of and ultimate fibrosis. Using Denileukin Diftitox alone highly up- Treg and Th2 cells, and decreased the number of Th17 cells [60]. regulated the expression of human inflammatory chemokines Another study showed that umbilical cord-derived MSCs selected McP-1 and MIP-1α in the liver [Fig. 2]. It revealed that McP-1, which by individual heterogeneity have the function of promoting Tregs is closely related to Tregs, may play an important role in the and have been proven to improve the recovery of liver fibrosis in process of fibrosis initiated by inflammation [45]. mice [61]. Tregs can also alleviate the pathological process of While protecting the body from physiological factors, inflam- hepatic steatosis and high-calibre abnormal blood cholesterol and matory cell immunity also promotes liver injury and fibrosis. Tregs glucose metabolism, and aberrant levels of liver enzymes in leptin- can inhibit inflammatory cell immunity, thereby inhibiting fibrosis. deficient OB/OB mice [62], indicating the potential curative effect It has been found that chronic liver inflammation induced by of diabetes and prevention of early hepatic fibrosis by carbon tetrachloride (CCL4) injection tends to preferentially inducing Tregs. expand liver Treg cells, thereby protecting liver function and In summary, the complex Treg interactome that induces an anti- avoiding fibrosis [46]. In CCL4-induced liver fibrosis, rapamycin has fibrotic effect involves the interaction between Tregs and a range an effective protective effect on the liver. Further studies found of liver cell types and signalling pathways. Rapamycin can that rapamycin significantly increased the functional activity of effectively protect the liver by enhancing the inhibitory ability of + + CD4 CD25 Treg, and enhanced the inhibitory ability of Tregs on Treg to the activation of HSCs. Tregs repress HSC activation by HSCs activation [47] [Fig. 2]. α-SMA is a hallmark of the activation repressing MCP-1-induced HSC activation and by repressing CD4 of HSCs and a sensitive indicator of myofibroblasts [48]. It was also T-cell secretion of IFN-γ. This anti-fibrotic interactome also found that increased Treg cell levels, induced by rapamycin, includes repression of Th2/IL-4 driven fibrosis, the repression of effectively decreased α-SMA expression [47]. Alternatively, Treg macrophage/TGF-β initiated fibrosis, and the promotion of hAMSC depletion enhances the immunologic function of inflammatory repression of fibrosis by promotion of TGF-β/IDO induced hAMSC. cells and drives pro-fibrotic T-helper 2 cells(Th2) that induce IL-4 Tregs repress fibrosis by inducing amphiregulin repression of activation. Th1 cells, which secrete IFN-γ and Th2 cells which fibrosis and Tregs can induce IL-2/CD39 repression of CD8 T-cells generate IL-4, are antifibrotic and pro-fibrotic T-helper cell subsets, to suppress fibrosis because they reduce CD8 T-cell expression of respectively. Treg depletion will break the balance between these TGF-α and osteopontin. It is, therefore, apparent that Tregs two subsets, thus leading to fibrosis [49]. Th2 cells and Ly- interact with multiple cell types in multiple pathways to repress high high 6C CCR2 inflammatory monocytes/macrophages both have liver fibrosis (Fig. 2). a pro-fibrotic function by secreting IL-4 and TGF-β respectively, although IL-10 secreted by Tregs may regulate them [50] [Fig. 2]. This illustrates that although Tregs can promote fibrosis, most THE TREG/TH17 BALANCE IN LIVER FIBROSIS evidence suggests that Treg cells have an anti-fibrotic effect, Th17 cells are a subpopulation of CD4 T cells that specifically primarily due to their immunosuppressive effect on IL-10 secretion express RORγt and secrete signature cytokines IL-17, IL-22, and IL- [51]. In addition, Tregs also secrete amphiregulin, an important 23 [63]. Recent studies have found that Th17 and the cytokines it factor involved in tissue repair and regeneration in a variety of secretes have a significant impact on the pathological process of models of inflammation [52]. In one study, amphiregulin inhibited liver fibrosis [64–66].Th17 cells are bound up with Treg cells. First, the development of fibrosis by promoting the proliferation of both Th17 and Treg cells are derived from naive CD4 T cells, and hepatocytes [53] [Fig. 2]. second, they both require TGF-β signalling to differentiate. In a model of acute disease induced by bile duct ligation(BDL), Interestingly, the two cells that are so similar have diametrically Tregs in the liver reduced T lymphocyte function and effectively contrary functions: Th17 cells contribute to the development of limited liver fibrosis [54] demonstrating the critical role of Tregs in inflammation and autoimmunity, while Treg cells suppress the maintaining immune suppression. Furthermore, in the BDL model, above-mentioned phenomena and promote immune homoeos- the exhaustion of Tregs increased the generation of inflammatory tasis [67] [Fig. 3]. In vitro HSCs can be activated by Th17 to develop mediators, such as chemokines and cytokines, and promoted the fibrosis while Tregs can inhibit the activation of HSCs [11]. infiltration of Th17 and CD8 T cells in the fibrotic liver [55], Some viruses can persistently damage liver tissue, eventually suggesting that Tregs can suppress the pro-fibrotic effects of Th17 leading to cirrhosis, and Treg/Th17 balance can prevent excessive and CD8 T cells. In a mouse model with sclerosing cholangitis, liver damage during viral infection. Some studies have found that treatment with low-dose IL-2 induced the expansion of intrahe- in acute hepatitis A virus(HAV) patients, serum IL-17 level has a patic Tregs, thereby reducing biliary injury and fibrosis. The positive correlation with the degree of liver damage, and the mechanism may be Il-2 precipitated, as well as its complexes, that frequency of hepatic resident and circulating Tregs is negatively promote Tregs expressing CD39 in the liver, thereby inhibiting the correlated with liver injury [68]. Similarly, other researchers have multiplication of CD8 T cells and its function of generating TNF-α demonstrated that the quantity and proportion of Th17 cells in and osteopontin, which can reduce biliary fibrosis [56] [Fig. 2]. the liver and peripheral blood are increased in acute and chronic Human amniotic mesenchymal stromal cells (hAMSC) can liver injury [69, 70] demonstrating the strong pro-fibrotic function regulate the immune response in a variety of diseases and of Th17. demonstrate a powerful regenerative repair ability similar to stem It has been found that a selective Rho/RhoA-associated kinase cells [57]. The combination of Treg and hAMSC infusion rescued (ROCK) inhibitor (Fasudil) can effectively inhibit cell differentiation low-grade liver fibrosis compared with injecting Treg or hAMSC of Th17 and its ability to express IL-17 [Fig. 3]. Using this inhibitor respectively. The reason may be that Tregs can improve the and the upregulation of Tregs can limit liver fibrosis in mice expression of hepatocyte growth factor (HGF) and the ability of caused by Schistosoma japonicum infection [71]. Treg/Th17 play hAMSC to differentiate [58] [Fig. 2]. The two principal cytokines opposite roles in the development of HBV-LF fibrosis by affecting expressed by Tregs are TGF-β and IL-10 [34, 59]. Experiments have liver injury and hematopoietic stem cell function [72]. This is shown that Tregs can regulate the TGF-β-IDO signalling pathway demonstrated, not only in liver fibrosis, but also proved that Treg/ and then enhance the function of hAMSC, and combination Th17 balance exists in several inflammatory and autoimmune therapy of Tregs and hAMSC infusion has great potential research diseases, including systemic lupus erythematosus (SLE), Cell Death Discovery (2023) 9:53 K. Wu et al. Fig. 3 The relationship between Tregs and Th17. Treg and Th17 cells are convertible in different immune microenvironments. Treg cells can be transformed into cells expressing IL-17 in the presence of IL-6 and IL-21, as well as IL-2 and IL-1β. Fasudil can effectively inhibit cell differentiation of Th17 and its ability to express IL-17. Using this inhibitor and upregulation of Treg can limit liver fibrosis in mice caused by Schistosoma japonicum infection. Rapamycin significantly reduced the level of Th17 cells in the CCL4-induced liver fibrosis model, it even can enhance the inhibitory function of Treg on HSCs.IL-35 has a similar function compared with the formers. Il-6 has an extraordinary effect on Th17/Treg balance. Il-6 can induce the development of naïve T cells into Th17 cells in the existence of TGF-β. However, its effect on Tregs has two sides. But overall, IL-6 still tilts the balance between Tregs and Th17 toward Th17 cells. DCs play dual roles in the pathways of Treg. Footnote: regulatory cells (Treg), T helper cell (Th), interleukin (IL), retinoid-related orphan receptor gamma t (RORγt), carbon tetrachloride (CCL4), hepatic stellate cells (HSCs), dendritic cells (DC). rheumatoid arthritis, and primary biliary cirrhosis, [73–75]. There- amplify the functions of virus-specific Treg cells while also fore, we deduce that the Treg/Th17 balance may be an important inhibiting Th17 cell differentiation [80] [Fig. 3]. It is this effect of biomarker of immune homoeostasis, reflecting some extent the IL-35 that could lead to the break of balance, which causes balance between the pro-inflammatory and anti-inflammatory persistent HBV infection and chronic disease, ultimately leading to abilities of the body. irreversible liver fibrosis. It was also found that rapamycin The balance of Treg /Th17 is so important in the progression of significantly reduced the level of Th17 cells and the expression cirrhosis that some scholars have considered it an independent level of ROR-γT in the CCL4-induced liver fibrosis model. At the predictor of decompensated cirrhosis [72]. It has also been same time, rapamycin can lead to a significant increase in Treg suggested that the Treg/Th17 ratio may be used as a measure of frequency and Foxp3 expression and it can even enhance the disease severity in animal models and human diseases [76]. Zhai inhibitory function of Tregs on HSCs [47] [Fig. 3]. From the et al. showed that the ratio of Th17 to Treg had a negative different effects of rapamycin on Treg and Th17 expression, as correlation with the survival rate of patients with acute-on-chronic well as its inhibition of the development of fibrosis, rapamycin liver failure(ACLF) [77]. The experimental results of Yu et al. also appears to play an important role in the regulation of Th17/Treg showed a similar conclusion, and they found that the ratio of Treg balance. to Th17 in the survival group was higher than the ratio in the non- As mentioned above, Tregs play different roles under different survival group of HBV-LC patients [78]. Nan et al. observed that cytokine conditions. However, increasing data indicate that Treg compared with the control group, the cell quantities of Treg and and Th17 cells are convertible in different immune microenviron- Th17 cells in the chronic HBV patients’ peripheral blood were ments. For instance, Treg cells can be transformed into cells larger, and the proliferation of Th17 cells was more obvious than expressing IL-17 in the presence of IL-6 and IL-21 [Fig. 3], while that of Treg cells in the acute attack, and this series of changes led Th17 cells can be transformed into Th1/2 cells in the existence of to the decrease of Treg/Th17 ratio [79]. Rong et al. reported that IL-4 or IL-12 [81]. Deknuydt et al found that nTregs can be the number of Th17 cells and the level of ROR-γT expression in the transformed into Th17 cells under the induction of IL-2 in the peripheral blood of patients suffering from primary biliary cirrhosis immune microenvironment where the activated APC and mono- were significantly increased. However, the quantity of Treg cells cytes after microbial stimulation are considered to be the most and the expression of FoxP3 were significantly decreased [73]. effective factors in promoting Treg transformation [Fig. 3]. Further Another study demonstrated that a lower ratio of Treg to Th17 studies showed that IL-1β could mediate the conversion of Tregs often indicates greater progression of liver fibrosis in HBV-infected to Th17 [Fig. 3], which may be related to the downregulation of patients [40]. These results suggest that the imbalance between Foxp3 [82]. Over the last few decades, the main research Th17 and Treg is strongly associated with the development of liver directions on liver fibrosis are Th1 and Th2-focused. Recent cirrhosis, and the balance of them may be a key prognostic advances in immunology have focused on two new T cell subsets indicator for HBV-LC, and an increased Treg/Th17 ratio may (Treg and Th17 cells) that supplement and refine the classical indicate a better prognosis, whereas a poor prognosis otherwise. theory of Th1/Th2 [83] interplay. For example, Il-6 has a significant In addition, lL-35 has a crucial impact on balancing Treg and effect on Th17/Treg balance [84] and can induce the development Th17 in acute and chronic HBV infection. It has been found to of naïve T cells into Th17 cells in the presence of TGF-β. On the Cell Death Discovery (2023) 9:53 K. Wu et al. contrary, IL-6 has both direct and indirect effects on Treg cells. On investigate different signalling pathways that may affect Th17/ the one hand, IL-6 suppressed the induction of Treg cell Tregs’ contribution to liver-specific therapies. Finally, we have conversion by TGF-β without affecting the number and function attempted to highlight the complex Treg interactome in its of nTregs [85, 86] [Fig. 3].On the other hand, there are several lines promotion of fibrosis, in its alternate anti-fibrotic role and lastly of evidence that IL-6 has immunomodulatory effects supporting how the Treg/Th17 ratio influences pro and anti-fibrotic activity. Tregs number and function, which are mainly because LPS- The multiplicity of interacting cells with Tregs in the liver, as well stimulated dendritic cells produce IL-6 which activates as the signalling pathways suggest that multiple therapeutic STAT3 signalling to eventually keep DCs in an immature state options can be further explored, however, a fuller understanding with low CD80 and MHC-II levels, as well as increase IL-10 of liver fibrogenesis will be needed. production to promote Treg cells [87] [Fig. 3]. But overall, IL-6 still tilts the balance between Tregs and Th17 toward Th17 cells. In summary, Th17 and Treg cells are integrally involved in the DATA AVAILABILITY immune response in the progression of liver fibrosis. Their balance All data included in this study are available upon request by contact with the determines the maintenance of body homoeostasis and is very corresponding author. important for the prevention or prognosis of liver fibrosis. 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Gut-derived commensal reprints bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin-6/signal transducer and activator of transcription 3 activity. Hepatol- Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims ogy. 2007;46:1946–59. in published maps and institutional affiliations. 88. Boveda-Ruiz D, D’Alessandro-Gabazza CN, Toda M, Takagi T, Naito M, Matsushima Y, et al. Differential role of regulatory T cells in early and late stages of pulmonary fibrosis. Immunobiology. 2013;218:245–54. 89. Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, et al. Circulating and liver resident Open Access This article is licensed under a Creative Commons CD4+CD25+ regulatory T cells actively influence the antiviral immune response Attribution 4.0 International License, which permits use, sharing, and disease progression in patients with hepatitis B. 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Regulatory T cells (Tregs) in liver fibrosis

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www.nature.com/cddiscovery REVIEW ARTICLE OPEN Regulatory T cells (Tregs) in liver fibrosis ✉ ✉ 1,7 2,7 2,7 1 1 3 4,5,6 1,6 Ke-jia Wu , Qu-fei Qian , Jin-ren Zhou , Dong-lin Sun , Yun-fei Duan , Xi Zhu , Kurt Sartorius and Yun-jie Lu © The Author(s) 2023 The ability of the human liver to both synthesize extracellular matrix(ECM), as well as regulate fibrogenesis, are integral functions to maintaining homoeostasis. Chronic liver injury stimulates fibrogenesis in response to the imbalance between ECM accumulation and fibrosis resolution. Liver disease that induces fibrogenesis is associated with multiple risk factors like hepatitis infection, schistosomiasis, alcohol, certain drugs, toxicants and emerging aetiology like diabetes and obesity. The activation of hepatic stellate cells (HSCs), whose function is to generate and accumulate ECM, is a pivotal event in liver fibrosis. Simultaneously, HSCs selectively promote regulatory T-cells (Tregs) in an interleukin-2–dependent pattern that displays a dual relationship. On the one hand, Tregs can protect HSCs from NK cell attack, while on the other hand, they demonstrate an inhibitory effect on HSCs. This paper reviews the dual role of Tregs in liver fibrogenesis which includes its promotion of immunosuppression, as well as its activation of fibrosis. In particular, the balance between Tregs and the Th17 cell population, which produce interleukin (IL)-17 and IL-22, is explored to demonstrate their key role in maintaining homoeostasis and immunoregulation. The contradictory roles of Tregs in liver fibrosis in different immune microenvironments and molecular pathways need to be better understood if they are to be deployed to manage this disease. Cell Death Discovery (2023) 9:53 ; https://doi.org/10.1038/s41420-023-01347-8 INTRODUCTION immune cells that respond to chronic inflammation, tissue Liver fibrosis is generally considered to be the consequence of regeneration, ECM remodelling and fibrogenesis [6]. A hallmark ongoing chronic liver injury and a leading pathogenic factor of event of liver fibrosis is the activation and expression of HSCs morbidity and mortality in chronic viral hepatitis and obesity- which are regulated by several immune mediators, including Th9, related fatty liver disease worldwide [1]. Non-resolving liver Th22, Tregs, innate lymphoid cells (ILCs), mucosal-associated fibrogenesis, stimulated by a wide range of risk factors, induces invariant T cells (MAIT), and γδT cells, along with their associated the activation of quiescent hepatic stellate cells (HSCs) into cytokines [7]. In early-stage fibrosis that is resolved, the immune myofibroblasts that are the primary extracellular matrix (ECM)-cell response contributes to terminating HSC activation and fibrous type that promotes fibrous protein deposition and scarring [2]. protein expression, however, in the case of ongoing liver disease, The severity and outcome of fibrogenesis in liver disease can be the complicated interplay of these immune mediators often triggered by a wide range of risk factors including viral infection, promotes liver fibrosis. A key change in the adaptive immune toxins, and a range of non-communicable diseases that contribute response is the mobilization of regulatory T(Tregs) cells that play to a build-up of fatty tissue in the liver. Chronic hepatitis infection, an immunosuppressive role to promote immune self-tolerance for instance, promotes liver fibrosis that can translate into cirrhosis and homoeostasis. The Treg family includes natural Tregs(nTregs) and the onset of neoplasms (Chronic hepatitis→ liver fibrosis→ that express the nuclear transcription factor FoxP3, as well as cell liver cirrhosis→ Liver Neoplasms) [3]. In patients suffering from surface proteins CTLA-4 and CD25 and induced Tregs(iTregs) [8, 9]. chronic liver injury, progression to the end stage usually takes 20 An increase of Tregs in fibroproliferative sites influences the to 40 years depending on whether both environmental and subsequent balance between tissue inhibitors of metalloproteina- genetic elements are causal factors [1]. Early-stage fibrosis is more se(TIMP) and matrix metalloproteinase(MMP) and Kupffer cell (KC) easily resolved while advanced liver fibrosis can result in a range expression to promote ECM remodelling and fibrogenesis [10]. In of severe symptoms, such as cirrhosis, liver failure, and portal addition, the Treg/TH17 ratio plays a key role in the process of hypertension [4], When fibrogenesis progresses to decompen- intrahepatic immune regulation and the dysregulation of this ratio sated cirrhosis, the survival period of patients is significantly is a key characteristic of the progression of liver fibrosis [7]. shortened, and therapeutic options are eventually limited to liver Restoring Treg/Th17 balance can effectively immunize against transplantation [5]. various intracorporal and extracorporeal pathogens, as well as Fibrogenesis as a result of liver injury involves a complex prevent excessive autoimmune self-harm [11]. However, further interactome that includes the interaction of various types of research on Tregs and the Treg/Th17 role in the fibrogenesis 1 2 Department of Hepatobiliary and Pancreatic Surgery, The Third Affiliated Hospital of Soochow University, Changzhou 213000, China. The First Affiliated Hospital of Nanjing 3 4 Medical University, Nanjing 210000, China. Department of infectious diseases, the First Peoples’ Hospital of Kunshan, 215300 Kunshan, China. Faculty of Commerce, Law and Management, University of the Witwatersrand, Johannesburg, South Africa. School of Laboratory Medicine and Molecular Sciences, University of Kwazulu-Natal, Durban, South 6 7 Africa. Africa Hepatopancreatobiliary Cancer Consortium, Mayo Clinic, Jacksonville, USA. These authors contributed equally: Ke-jia Wu, Qu-fei Qian, Jin-ren Zhou. email: sin0112@163.com; lyj0001@suda.edu.cn Received: 23 November 2022 Revised: 24 January 2023 Accepted: 27 January 2023 Official journal of CDDpress 1234567890();,: K. Wu et al. Fig. 1 The role of Treg in promoting fibrosis. Liver fibrosis is primarily induced by HSCs that promote TGF-β based production of myofibroblasts that stimulate ECM-driven fibrogenesis. Tregs can also activate HSCs to promote fibrosis through the TGF-β pathway. Treg can + + + induce HSCs via the expression of IL-8. Treg cells with CD4 CD25 Foxp3 can be selectively expanded by HSCs in an IL-2–dependent pattern. Tregs can directly suppress NK cells from degranulating in the role of IL-8, TGF-β1, and CTLA-4 signalling pathways. Footnote: hepatic stellate cells (HSCs), transforming growth factor-β (TGF-β), extracellular matrix (ECM), matrix metalloproteinase (MMP), regulatory cells (Treg), kupffer call (KC), interleukin-2 (IL-2), natural killer cell (NK cell), cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). interactome is needed to promote potential diagnostic and surface: CD25, CTLA-4, PD-L1, GITR, and HLA-DR [20, 21]. The therapeutic options. This review outlines the current under- expression and functions have significant differences between standing of the role/s of Tregs on liver fibrosis. First, we review the naïve and activated Tregs, suggesting another dimension that the known pathways of Tregs that promote fibrogenesis and second tissue Tregs express higher levels of activation markers compared the role of Tregs and their related cytokines that suppress to blood. For example, activated effector Tregs (CD45RA- fibrogenesis. Thirdly, we outline the potential effects of the Treg/ FOXP3high) express high levels of HLA-DR compared to naïve Th17 balance and their related cytokines on fibrogenesis and Tregs (CD45RA FOXP3low) [22, 23] and activated Treg cells play a finally, we illustrate the complex Treg interactome and discuss the major role in fibrogenesis. Although Treg cells only account for potential for Treg therapy to be exploited for the treatment of 5%-10% of the total CD4 T lymphocytes in peripheral blood [24], fibrosis of the liver. their contribution to maintaining immune tolerance and homo- eostasis cannot be ignored. BACKGROUND AND ROLE OF TREGS Treg cells were first discovered by GERSHON et al. [12] in the THE PRO-FIBROSIS FUNCTION OF TREG 1970s and were referred to as “suppressor cells” because of their Activated Tregs are essential during the healing period to end role in immune regulation. A later study in 1995 showed that inflammation and promote wound healing [25] and yet recent CD25 expression was a hallmark of these suppressor cells that evidence indicates that a large number of Tregs are distributed in were labelled for the first time as Tregs [13]. This study also the fibrotic microenvironment in HCC patients. Interestingly, a + + demonstrated that the in vivo transfer of CD4 CD25 Treg- reduction in Tregs promoted the regression of fibrosis [26] deficient T cells triggered autoimmune disease in a mouse model. illustrating that Tregs play a prominent role in promoting fibrosis + + + + + Conversely, autoimmune effects were retarded when CD4 CD25 [Fig. 1]. A report showed Treg cells with CD4 CD25 Foxp3 were cells were introduced. The prevailing view is that there are two selectively increased by HSCs in an interleukin-2–dependent main sub-types of Tregs determined by cellular origin, namely, pattern [27] explaining the abundance of Tregs in fibrotic tissue natural Tregs(nTregs), which are differentiated in the thymus from [Fig. 1]. MMPs, the main enzyme involved in ECM degradation [28] progenitor cells derived from bone marrow, and inducible Tregs are produced primarily by KCs [29], however, even a low ratio of (iTregs), which are differentiated from peripheral naïve T cells to Tregs can repress KC expression of MMPs. Treg cells regulate the respond to infectious challenges. Except for nTregs and iTregs, balance of MMP/TIMP through KCs, thereby inhibiting the various studies have identified other T cells with regulatory resolution of fibrosis [4] [Fig. 1]. properties, including T helper (Th)-like Treg subsets, CD8 Tregs, Experiments have shown that Tregs may inhibit KCs from Tr1 cells, and Th3 cells [14–17]. In addition, many researchers have secreting MMP in vivo through the TGF-β pathway [30] [Fig. 1]. A subdivided Treg cells into different subsets in different diseases parallel increase in collagen type I deposition and TGF-β1 Tre g according to the different expression of Treg cell surface cells was observed in lymphoid tissues of the simian immunode- molecules, such as “Treg B” that shows a higher expression of ficiency virus (SIV) -infected rhesus monkeys 7 days after inocula- hi lo + CD95, CCR4, and CD45RO within FOXP3 , CD127 Tregs in tion [31]. These results indicate that TGF-β1 Treg cells have a aplastic anaemia [18]. Transcription factor forkhead box protein 3 dichotomous response to immune activation; on the one hand, (FoxP3) is the most characteristic marker of Treg cells and plays an they can inhibit viral immune response while on the other hand, important role in Treg development and immune regulation. Tregs they can induce collagen deposition in lymphoid tissues, resulting mainly secrete IL-10, TGF-β, IL-35, and other cytokines, which in organ fibrosis. enable the body to obtain immune tolerance by inhibiting the HSCs which are spread over the Disse space are generally differentiation and proliferation of NKT cells, macrophages, B cells, considered to be the hallmark cells of fibrosis and the major and so on [19]. Treg cells express the following molecules on their source of myofibroblasts and activation of HSCs is the initiating Cell Death Discovery (2023) 9:53 K. Wu et al. Fig. 2 The role of Treg in inhibiting fibrosis. IL-2 as well as its complexes accelerate Tregs expressing CD39 in the liver, thereby inhibiting the multiplication of CD8 T cells and its function of generating TNF-α and osteopontin, which can reduce biliary fibrosis. Tregs can regulate the high high pro-fibrotic roles of Th2 cells and Ly-6C CCR2 inflammatory monocytes/macrophages that secrete IL-4 and TGF-β respectively, interestingly, IL-10 secreted by Tregs may regulate them. Tregs can regulate the TGF-β-IDO signalling pathway to enhance the function of hAMSC that repress liver fibrosis. Tregs promoting the expression of amphiregulin can inhibit the development of fibrosis by promoting the proliferation of hepatocytes. In CCL4-induced liver fibrosis, rapamycin has an effective protective effect on the liver. Rapamycin significantly + + increased the functional activity of CD4 CD25 Tregs and enhanced the inhibitory ability of Tregs on HSCs activation. Tregs can repress MCP- 1 which plays an important role in liver fibrosis by activating HSC production. Tregs can directly repress CD4 T cell expression that reduces IFN-γ activated HSCs. Tregs also directly promote amphiregulin to repress liver fibrosis. Footnote: interleukin (IL), regulatory cells (Treg), transforming growth factor-α (TGF-α), T helper cell (Th), indoleamine 2,3-dioxygenase (IDO), human amniotic mesenchymal stromal cell (hAMSC), carbon tetrachloride(CCL4), hepatic stellate cells (HSCs), monocyte chemotactic protein-1 (MCP-1), Interferon-γ (IFN-γ). event of hepatic fibrosis. HSCs themselves can regulate the and α-SMA regions), it has also been demonstrated that deletion development of fibrosis. On the one hand, in the presence of of IL-8 can inhibit the activation of HSCs, however, the immune inflammatory stimuli, resting HSCs are often activated and regulatory function of Treg cells was not affected, illustrating that converted into myofibroblast-like cells and generate large IL-8 Tregs can promote fibrosis [39] [Fig. 1]. amounts of ECM and cytokines [Fig. 1]. On the other hand, In summary, the complex Treg interactome reveals that Treg activated HSCs can secrete MMPs to degrade ECM [32] [Fig. 1]. It expression can secrete IL-8 to activate HSCs that, in turn, can can be said that HSCs largely determine the promotion or secrete IL-2 to induce Treg expression. Tregs can secrete TGF- β to regression of liver fibrosis. In addition, TGF-β1 secreted by repress KC expression of MMPs that degrade ECM accumulation to macrophages is the strongest known activator of HSCs [33]. promote fibrogenesis and Treg-secreted TGF- β promotes HSC- Meanwhile, the two most important cytokines secreted by Tregs derived myofibroblasts. Tregs also promote fibrogenesis by are TGF-β and IL-10 [34] and Tregs can activate HSCs to promote secreting Il-8, TGF- β and CTLA-4 to repress NK repression of fibrosis through the TGF-β pathway [Fig. 1]. HSC activation. Tregs thus interact with multiple cell types and Of note, HBV which is one of the main pathogenic factors activate a range of cell–cell interactions with HSCs, NKs and KCs to leading to liver fibrosis can induce the generation of immuno- promote fibrogenesis (Fig. 1). suppressive cells, such as Tregs, MDSCs, and NK-REG cells, through the immunosuppressive cascade, undue induction can lead to adverse outcomes, such as liver fibrosis and even HCC [35]. HBV- THE ANTI-FIBROSIS FUNCTION OF TREG induced Tregs may suppress the antifibrotic function of NK cells It is interesting to note that TGF-β generated by Tregs in HCV is and directly suppress NK cells from degranulating in the role of IL- inversely associated with the regression of liver inflammation and 8, TGF-β1, and CTLA-4 signalling pathways [Fig. 1]. Tregs can also fibrosis, even though cytokine TGF-β is a well-established pro- have an indirect protective effect on HSCs from NK cell’s attack on fibrotic element, suggesting that TGF-β also has antifibrotic account of suppressing the expression of MICA/B on HSCs through properties [40]. According to the observation, the large number TGF-β1 and IL-8 [36]. Tregs can inhibit NK cells and M1 KCs from of highly differentiated and activated Tregs distributed to participating in the immune regulation of liver fibrosis, and its infiltrating chronic HCV-infected livers can lead to a limitation of immunosuppressive regulation contributes to the development of the degree of fibrosis. [41] Tregs in the peripheral blood of HCV chronic inflammation, thus maintaining liver fibrosis [37]. There- patients can suppress the proliferation of HCV-specific T cells and fore, by cutting off the pathway of Treg action on NK cells and IFN-γ [42]. In addition, the depletion of Tregs restored the restoring antiviral T-cell responses, the development of inflamma- secretion of IFN-γ by CD4 T cells [43] [Fig. 2]. This indicates that tion and injury can be limited, and HSCs, as a crucial element of Tregs in an HCV-induced environment are pivotal in the limitation liver fibrosis, can be reduced, thereby limiting the development of of collateral injury and homoeostasis maintenance by inhibiting liver fibrosis. an intemperate immune response. In addition, according to experimental observation, Treg cells Treg cells can guard against HIV-1-induced liver fibrosis, and the have been shown to proliferate during chronic HCV infection [38] mechanism may be related to the activation of HSCs, liver injury, and are enriched in liver fibrosis tissue to protect HSCs from NK and hepatitis [44]. In this regard, one study investigating HIV-1- cell attack [36]. Interestingly, an abundance of T cells with induced liver fibrosis deleted Treg cells with denileukin diftitox. By + + + IL-8 CD4 Foxp3 are found in HCV liver tissue (mainly in fibrotic measuring various plasma indicators, Only HIV-1+ denileukin Cell Death Discovery (2023) 9:53 K. Wu et al. diftitox mice in infection showed a significant increase in ALT value for the treatment of liver cirrhosis [58] [Fig. 2]. It was also levels after 20 days. Similarly, serum hyaluronic acid levels, also a proved that mesenchymal stem cells(MSCs) as well as MSC- sign of liver injury and fibrosis, were only elevated in infected HIV- conditioned medium (MSC-CM) both inhibited necroinflammatory 1+ denileukin diftitox mice after 20 days. Therefore, HIV-1 and fibrogenesis in a chronic liver injury model, however, the infection together with Tregs depletion causes liver inflammation second therapy had a better effect. In this regard, the activation of and ultimate fibrosis. Using Denileukin Diftitox alone highly up- Treg and Th2 cells, and decreased the number of Th17 cells [60]. regulated the expression of human inflammatory chemokines Another study showed that umbilical cord-derived MSCs selected McP-1 and MIP-1α in the liver [Fig. 2]. It revealed that McP-1, which by individual heterogeneity have the function of promoting Tregs is closely related to Tregs, may play an important role in the and have been proven to improve the recovery of liver fibrosis in process of fibrosis initiated by inflammation [45]. mice [61]. Tregs can also alleviate the pathological process of While protecting the body from physiological factors, inflam- hepatic steatosis and high-calibre abnormal blood cholesterol and matory cell immunity also promotes liver injury and fibrosis. Tregs glucose metabolism, and aberrant levels of liver enzymes in leptin- can inhibit inflammatory cell immunity, thereby inhibiting fibrosis. deficient OB/OB mice [62], indicating the potential curative effect It has been found that chronic liver inflammation induced by of diabetes and prevention of early hepatic fibrosis by carbon tetrachloride (CCL4) injection tends to preferentially inducing Tregs. expand liver Treg cells, thereby protecting liver function and In summary, the complex Treg interactome that induces an anti- avoiding fibrosis [46]. In CCL4-induced liver fibrosis, rapamycin has fibrotic effect involves the interaction between Tregs and a range an effective protective effect on the liver. Further studies found of liver cell types and signalling pathways. Rapamycin can that rapamycin significantly increased the functional activity of effectively protect the liver by enhancing the inhibitory ability of + + CD4 CD25 Treg, and enhanced the inhibitory ability of Tregs on Treg to the activation of HSCs. Tregs repress HSC activation by HSCs activation [47] [Fig. 2]. α-SMA is a hallmark of the activation repressing MCP-1-induced HSC activation and by repressing CD4 of HSCs and a sensitive indicator of myofibroblasts [48]. It was also T-cell secretion of IFN-γ. This anti-fibrotic interactome also found that increased Treg cell levels, induced by rapamycin, includes repression of Th2/IL-4 driven fibrosis, the repression of effectively decreased α-SMA expression [47]. Alternatively, Treg macrophage/TGF-β initiated fibrosis, and the promotion of hAMSC depletion enhances the immunologic function of inflammatory repression of fibrosis by promotion of TGF-β/IDO induced hAMSC. cells and drives pro-fibrotic T-helper 2 cells(Th2) that induce IL-4 Tregs repress fibrosis by inducing amphiregulin repression of activation. Th1 cells, which secrete IFN-γ and Th2 cells which fibrosis and Tregs can induce IL-2/CD39 repression of CD8 T-cells generate IL-4, are antifibrotic and pro-fibrotic T-helper cell subsets, to suppress fibrosis because they reduce CD8 T-cell expression of respectively. Treg depletion will break the balance between these TGF-α and osteopontin. It is, therefore, apparent that Tregs two subsets, thus leading to fibrosis [49]. Th2 cells and Ly- interact with multiple cell types in multiple pathways to repress high high 6C CCR2 inflammatory monocytes/macrophages both have liver fibrosis (Fig. 2). a pro-fibrotic function by secreting IL-4 and TGF-β respectively, although IL-10 secreted by Tregs may regulate them [50] [Fig. 2]. This illustrates that although Tregs can promote fibrosis, most THE TREG/TH17 BALANCE IN LIVER FIBROSIS evidence suggests that Treg cells have an anti-fibrotic effect, Th17 cells are a subpopulation of CD4 T cells that specifically primarily due to their immunosuppressive effect on IL-10 secretion express RORγt and secrete signature cytokines IL-17, IL-22, and IL- [51]. In addition, Tregs also secrete amphiregulin, an important 23 [63]. Recent studies have found that Th17 and the cytokines it factor involved in tissue repair and regeneration in a variety of secretes have a significant impact on the pathological process of models of inflammation [52]. In one study, amphiregulin inhibited liver fibrosis [64–66].Th17 cells are bound up with Treg cells. First, the development of fibrosis by promoting the proliferation of both Th17 and Treg cells are derived from naive CD4 T cells, and hepatocytes [53] [Fig. 2]. second, they both require TGF-β signalling to differentiate. In a model of acute disease induced by bile duct ligation(BDL), Interestingly, the two cells that are so similar have diametrically Tregs in the liver reduced T lymphocyte function and effectively contrary functions: Th17 cells contribute to the development of limited liver fibrosis [54] demonstrating the critical role of Tregs in inflammation and autoimmunity, while Treg cells suppress the maintaining immune suppression. Furthermore, in the BDL model, above-mentioned phenomena and promote immune homoeos- the exhaustion of Tregs increased the generation of inflammatory tasis [67] [Fig. 3]. In vitro HSCs can be activated by Th17 to develop mediators, such as chemokines and cytokines, and promoted the fibrosis while Tregs can inhibit the activation of HSCs [11]. infiltration of Th17 and CD8 T cells in the fibrotic liver [55], Some viruses can persistently damage liver tissue, eventually suggesting that Tregs can suppress the pro-fibrotic effects of Th17 leading to cirrhosis, and Treg/Th17 balance can prevent excessive and CD8 T cells. In a mouse model with sclerosing cholangitis, liver damage during viral infection. Some studies have found that treatment with low-dose IL-2 induced the expansion of intrahe- in acute hepatitis A virus(HAV) patients, serum IL-17 level has a patic Tregs, thereby reducing biliary injury and fibrosis. The positive correlation with the degree of liver damage, and the mechanism may be Il-2 precipitated, as well as its complexes, that frequency of hepatic resident and circulating Tregs is negatively promote Tregs expressing CD39 in the liver, thereby inhibiting the correlated with liver injury [68]. Similarly, other researchers have multiplication of CD8 T cells and its function of generating TNF-α demonstrated that the quantity and proportion of Th17 cells in and osteopontin, which can reduce biliary fibrosis [56] [Fig. 2]. the liver and peripheral blood are increased in acute and chronic Human amniotic mesenchymal stromal cells (hAMSC) can liver injury [69, 70] demonstrating the strong pro-fibrotic function regulate the immune response in a variety of diseases and of Th17. demonstrate a powerful regenerative repair ability similar to stem It has been found that a selective Rho/RhoA-associated kinase cells [57]. The combination of Treg and hAMSC infusion rescued (ROCK) inhibitor (Fasudil) can effectively inhibit cell differentiation low-grade liver fibrosis compared with injecting Treg or hAMSC of Th17 and its ability to express IL-17 [Fig. 3]. Using this inhibitor respectively. The reason may be that Tregs can improve the and the upregulation of Tregs can limit liver fibrosis in mice expression of hepatocyte growth factor (HGF) and the ability of caused by Schistosoma japonicum infection [71]. Treg/Th17 play hAMSC to differentiate [58] [Fig. 2]. The two principal cytokines opposite roles in the development of HBV-LF fibrosis by affecting expressed by Tregs are TGF-β and IL-10 [34, 59]. Experiments have liver injury and hematopoietic stem cell function [72]. This is shown that Tregs can regulate the TGF-β-IDO signalling pathway demonstrated, not only in liver fibrosis, but also proved that Treg/ and then enhance the function of hAMSC, and combination Th17 balance exists in several inflammatory and autoimmune therapy of Tregs and hAMSC infusion has great potential research diseases, including systemic lupus erythematosus (SLE), Cell Death Discovery (2023) 9:53 K. Wu et al. Fig. 3 The relationship between Tregs and Th17. Treg and Th17 cells are convertible in different immune microenvironments. Treg cells can be transformed into cells expressing IL-17 in the presence of IL-6 and IL-21, as well as IL-2 and IL-1β. Fasudil can effectively inhibit cell differentiation of Th17 and its ability to express IL-17. Using this inhibitor and upregulation of Treg can limit liver fibrosis in mice caused by Schistosoma japonicum infection. Rapamycin significantly reduced the level of Th17 cells in the CCL4-induced liver fibrosis model, it even can enhance the inhibitory function of Treg on HSCs.IL-35 has a similar function compared with the formers. Il-6 has an extraordinary effect on Th17/Treg balance. Il-6 can induce the development of naïve T cells into Th17 cells in the existence of TGF-β. However, its effect on Tregs has two sides. But overall, IL-6 still tilts the balance between Tregs and Th17 toward Th17 cells. DCs play dual roles in the pathways of Treg. Footnote: regulatory cells (Treg), T helper cell (Th), interleukin (IL), retinoid-related orphan receptor gamma t (RORγt), carbon tetrachloride (CCL4), hepatic stellate cells (HSCs), dendritic cells (DC). rheumatoid arthritis, and primary biliary cirrhosis, [73–75]. There- amplify the functions of virus-specific Treg cells while also fore, we deduce that the Treg/Th17 balance may be an important inhibiting Th17 cell differentiation [80] [Fig. 3]. It is this effect of biomarker of immune homoeostasis, reflecting some extent the IL-35 that could lead to the break of balance, which causes balance between the pro-inflammatory and anti-inflammatory persistent HBV infection and chronic disease, ultimately leading to abilities of the body. irreversible liver fibrosis. It was also found that rapamycin The balance of Treg /Th17 is so important in the progression of significantly reduced the level of Th17 cells and the expression cirrhosis that some scholars have considered it an independent level of ROR-γT in the CCL4-induced liver fibrosis model. At the predictor of decompensated cirrhosis [72]. It has also been same time, rapamycin can lead to a significant increase in Treg suggested that the Treg/Th17 ratio may be used as a measure of frequency and Foxp3 expression and it can even enhance the disease severity in animal models and human diseases [76]. Zhai inhibitory function of Tregs on HSCs [47] [Fig. 3]. From the et al. showed that the ratio of Th17 to Treg had a negative different effects of rapamycin on Treg and Th17 expression, as correlation with the survival rate of patients with acute-on-chronic well as its inhibition of the development of fibrosis, rapamycin liver failure(ACLF) [77]. The experimental results of Yu et al. also appears to play an important role in the regulation of Th17/Treg showed a similar conclusion, and they found that the ratio of Treg balance. to Th17 in the survival group was higher than the ratio in the non- As mentioned above, Tregs play different roles under different survival group of HBV-LC patients [78]. Nan et al. observed that cytokine conditions. However, increasing data indicate that Treg compared with the control group, the cell quantities of Treg and and Th17 cells are convertible in different immune microenviron- Th17 cells in the chronic HBV patients’ peripheral blood were ments. For instance, Treg cells can be transformed into cells larger, and the proliferation of Th17 cells was more obvious than expressing IL-17 in the presence of IL-6 and IL-21 [Fig. 3], while that of Treg cells in the acute attack, and this series of changes led Th17 cells can be transformed into Th1/2 cells in the existence of to the decrease of Treg/Th17 ratio [79]. Rong et al. reported that IL-4 or IL-12 [81]. Deknuydt et al found that nTregs can be the number of Th17 cells and the level of ROR-γT expression in the transformed into Th17 cells under the induction of IL-2 in the peripheral blood of patients suffering from primary biliary cirrhosis immune microenvironment where the activated APC and mono- were significantly increased. However, the quantity of Treg cells cytes after microbial stimulation are considered to be the most and the expression of FoxP3 were significantly decreased [73]. effective factors in promoting Treg transformation [Fig. 3]. Further Another study demonstrated that a lower ratio of Treg to Th17 studies showed that IL-1β could mediate the conversion of Tregs often indicates greater progression of liver fibrosis in HBV-infected to Th17 [Fig. 3], which may be related to the downregulation of patients [40]. These results suggest that the imbalance between Foxp3 [82]. Over the last few decades, the main research Th17 and Treg is strongly associated with the development of liver directions on liver fibrosis are Th1 and Th2-focused. Recent cirrhosis, and the balance of them may be a key prognostic advances in immunology have focused on two new T cell subsets indicator for HBV-LC, and an increased Treg/Th17 ratio may (Treg and Th17 cells) that supplement and refine the classical indicate a better prognosis, whereas a poor prognosis otherwise. theory of Th1/Th2 [83] interplay. For example, Il-6 has a significant In addition, lL-35 has a crucial impact on balancing Treg and effect on Th17/Treg balance [84] and can induce the development Th17 in acute and chronic HBV infection. It has been found to of naïve T cells into Th17 cells in the presence of TGF-β. On the Cell Death Discovery (2023) 9:53 K. Wu et al. contrary, IL-6 has both direct and indirect effects on Treg cells. On investigate different signalling pathways that may affect Th17/ the one hand, IL-6 suppressed the induction of Treg cell Tregs’ contribution to liver-specific therapies. Finally, we have conversion by TGF-β without affecting the number and function attempted to highlight the complex Treg interactome in its of nTregs [85, 86] [Fig. 3].On the other hand, there are several lines promotion of fibrosis, in its alternate anti-fibrotic role and lastly of evidence that IL-6 has immunomodulatory effects supporting how the Treg/Th17 ratio influences pro and anti-fibrotic activity. Tregs number and function, which are mainly because LPS- The multiplicity of interacting cells with Tregs in the liver, as well stimulated dendritic cells produce IL-6 which activates as the signalling pathways suggest that multiple therapeutic STAT3 signalling to eventually keep DCs in an immature state options can be further explored, however, a fuller understanding with low CD80 and MHC-II levels, as well as increase IL-10 of liver fibrogenesis will be needed. production to promote Treg cells [87] [Fig. 3]. But overall, IL-6 still tilts the balance between Tregs and Th17 toward Th17 cells. In summary, Th17 and Treg cells are integrally involved in the DATA AVAILABILITY immune response in the progression of liver fibrosis. Their balance All data included in this study are available upon request by contact with the determines the maintenance of body homoeostasis and is very corresponding author. important for the prevention or prognosis of liver fibrosis. 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The ratio of Th-17 to Treg article and approved the submitted version. cells is associated with survival of patients with acute-on-chronic hepatitis B liver failure. Viral Immunol. 2011;24:303–10. 78. Yu X, Guo R, Ming D, Su M, Lin C, Deng Y, et al. Ratios of regulatory T cells/T- FUNDING helper 17 cells and transforming growth factor-β1/interleukin-17 to be associated This work was supported by the National Natural Science Foundation of China with the development of hepatitis B virus-associated liver cirrhosis. J Gastro- (81971504), Changzhou Top Health Talents Project (KY20221374), Jiangsu Science enterol Hepatol. 2014;29:1065–72. and Technology Talent Promotion Project (TJ2022052), Changzhou International 79. Nan XP, Zhang Y, Yu HT, Sun RL, Peng MJ, Li Y, et al. Inhibition of viral replication Science and Technology Cooperation Project (CZ20220032), The lifting Project of downregulates CD4(+)CD25(high) regulatory T cells and programmed death- Young Scientific and technological talents in Changzhou (KY20211103), Sino-German ligand 1 in chronic hepatitis B. Viral Immunol. 2012;25:21–8. Center Project (GZ1600), Changzhou Society Development Funding (CE20205038), 80. Yang L, Jia S, Shao X, Liu S, Zhang Q, Song J, et al. Interleukin-35 modulates Jiangsu Postdoctoral Talent Project (2020Z021). the balance between viral specificCD4(+)CD25(+)CD127(dim/-) regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection. Virol J. 2019;16:48. COMPETING INTERESTS 81. Zhou L, Chong MM, Littman DR. Plasticity of CD4+ T cell lineage differentiation. The authors declare no competing interests. Immunity 2009;30:646–55. 82. Deknuydt F, Bioley G, Valmori D, Ayyoub M. IL-1beta and IL-2 convert human Treg into T(H)17 cells. 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Gut-derived commensal reprints bacterial products inhibit liver dendritic cell maturation by stimulating hepatic interleukin-6/signal transducer and activator of transcription 3 activity. Hepatol- Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims ogy. 2007;46:1946–59. in published maps and institutional affiliations. 88. Boveda-Ruiz D, D’Alessandro-Gabazza CN, Toda M, Takagi T, Naito M, Matsushima Y, et al. Differential role of regulatory T cells in early and late stages of pulmonary fibrosis. Immunobiology. 2013;218:245–54. 89. Xu D, Fu J, Jin L, Zhang H, Zhou C, Zou Z, et al. Circulating and liver resident Open Access This article is licensed under a Creative Commons CD4+CD25+ regulatory T cells actively influence the antiviral immune response Attribution 4.0 International License, which permits use, sharing, and disease progression in patients with hepatitis B. 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ACKNOWLEDGEMENTS We would like to show sincere appreciation to the anonymous reviewers for their many useful comments on the early version of the manuscript. © The Author(s) 2023 Cell Death Discovery (2023) 9:53

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