Thelper 17 cell: A distinctive cell in liver diseases

Hepatology Research 2011; 41: 22–29

doi: 10.1111/j.1872-034X.2010.00744.x

Review Article

T-helper 17 cell: A distinctive cell in liver diseases

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Chao Ye, Wen-yuan Li, Ming-hua Zheng and Yong-ping Chen Department of Infection and Liver Diseases, Liver Research Center, First Affiliated Hospital of Wenzhou Medical College, Wenzhou, China

T-helper (Th)17 cells, a new population of effector CD4+ T cells, are characterized by the secretion of interleukin (IL)-17. It has been demonstrated that Th17 cells are distinct from Th1 and Th2 cells; they play important roles in the pathogenesis of numerous inflammatory and autoimmune diseases; and are closely related to host defense, tumorigenesis and transplant rejection. Moreover, it has been found that these cells have a close and intricate connection with the regulatory T cells,

which play an important role in maintaining self-tolerance and down-tuning immune responses. In the present review, we find that they are significantly elevated in various kinds of liver diseases including liver autoimmunity and inflammatory diseases, alcoholic liver disease and hepatocellular carcinoma.

INTRODUCTION

has been found that a close relationship exists between Th17 and Treg cells (Fig. 2). Nowadays, more and more evidences suggest that Th17 cells are implicated in pathogenesis of numerous inflammatory and autoimmune diseases,10 host defense, tumorigenesis and transplant rejection.11 Initially, the relationship between Th17 cells and liver diseases has gathered much attention. In this article, we review the latest findings related to Th17 cells in liver diseases.

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ARLY STUDIES HAVE demonstrated that CD4+ T cells could polarize into two different subsets, T-helper cell (Th)1 cells and Th2 cells.1 These two types of cells represent mutually exclusive differentiation programs undertaken by CD4+ T cells during immune responses.2 Th1 cells produce signature cytokine g-interferon (INF-g) and are responsible for immunity against intracellular pathogens with the risk of causing autoimmune diseases,3,4 while Th2 cells secrete interleukin (IL)-4, IL-5 and IL-13 which provide immunity against extracellular pathogens with the risk of causing allergic responses.5,6 In recent years, a new population of effector CD4+ T cells characterized by the secretion of IL-17, Th17 cells, has been demonstrated to be distinct from Th1 and Th2 cells in phenotype, function and development pathway.7,8 In addition, another distinct subset of CD4+ T cell–regulatory T cells (Treg) play an important role in maintaining self-tolerance and downtune immune responses through their inhibitory functions on effector cells.9 The Th1, Th2, Th17 and Treg cells are generated from the same precursors (Fig. 1). It

Correspondence: Dr Yong-Ping Chen, Department of Infection and Liver Diseases, Liver Research Center, First Affiliated Hospital of Wenzhou Medical College, 2 Fuxue Lane, Wenzhou, Zhejiang Province 325000, China. Email: [email protected] Received 12 August 2010; revision 8 October 2010; accepted 15 October 2010.

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Key words: autoimmune, inflammatory, liver, regulatory T cell, T-helper 17 cell.

OVERVIEW OF TH17 Differentiation and function of Th17 cells

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HILE A CLEAR role of Th17/IL-17 had been established, the factors that were necessary for their differentiation from naive T cells had yet been fully understood. Although early studies had suggested that IL-23 was fundamental for survival and for terminal differentiation of Th17 cells, it quickly became clear that this cytokine was important for the Th17 subset but not for naive T cells. The expression of IL-23 is only in activated Th17 cells.12 Researches from three groups independently showed that the suppressive cytokine transforming growth factor (TGF)-b together with the inflammatory cytokine IL-6 can induce the differentiation of naive T cells into the Th17 phenotype, and this procedure can not be done by TGF-b alone, which implicated that IL-6 is crucial for the differentiation of Th17 cells.13–15 In humans, it was initially suggested that

© 2010 The Japan Society of Hepatology


Th17 cells and liver diseases

β F- id TG ac 0 c -1 oi IL tin Re

Pro-inflammatory cytokine production Treg

IL-17 IL-21 IL-22 IL-26 TNF-α

Inhibition of clonal expansion IL-10 TGF-β of effective T cell populations

Figure 1 Possible differentiation pathways of naive CD4+ T cells under different stimulation. IFN-g, g-interferon; IL, interleukin; TGF-b, transforming growth factor-b; Th1 and Th2, T helper cells 1 and 2; TNF-a, tumor necrosis factor-a; Treg, regulatory T cells.

β F-

Signaling of innate cytokines was usually transducted through particular members of the signal transductor and activator of transcription (STAT) family to initiate lineage-specific transcriptional programs, such as Th1 and Th2 differentiation. Recent studies of Th17 cells have shown that their differentiation does not depend on STAT1, STAT4 and/or STAT6, and they do not express any conventional transcriptional factor involved in Th1 and Th2 differentiation.7,8 However, the cytokines that induce Th17 differentiation such as IL-6, IL-21 and IL-23 do induce phosphorylation of STAT3. It has been demonstrated that STAT3 can directly bind to the promoter region of IL-17. Furthermore, it has been reported that the deficiency of suppressor of cytokine signaling 3

Naive T cells

Th-17

Treg ( inhibit ) FoxP3

ROR-gt Unbalance

17 IL-

Signaling and transcription factors in Th17 cells

In 1995, Sakaguchi et al.27 found that Treg cells are a new subset of T cells, comparing them with Th1, Th2

TG

TGF-b may not induce but even inhibit the differentiation of human Th17 cells, while IL-1 and IL-6 played key roles in this process.16 Investigations also reported on the importance of IL-1 and IL-23 as differentiation and survival factors of Th17 cells in murine and human studies (Fig. 1).17,18 Nevertheless, it is also known that several other cytokines may interfere with the development and proliferation of Th17 cells, such as INF-g, IL-4 and Th1, Th2-promoting stimulus, negatively regulated Th cells producing IL-17. Under the Th1 and Th2 polarization condition, IL-23 treatment also hardly increased the number of IL-17 producing cells. Then, it was demonstrated that IL-13, IL-25 and IL-27 have inhibitory functions on Th17 development.8,19,20

Connection between Th17 and Treg cells

F-β

Th 17

TG

IL-4 IL-5 IL-13

Fβ

Response to extracellular pathogens

Th2

(SOCS3), that is a negative regulator of STAT3 phosphorylation, significantly enhances IL-17 expression in both murine and human subjects.21–24 Because IL-6/IL-21 together with TGF-b induce Th17 cells as we described before, the signaling inputs provided by TGF-b receptor to induce Th17 cell differentiation still remain to be established. A recent study suggested that under steady state conditions, human T cells are constitutively stimulated by TGF-b as revealed by detection of phosphorylated SMAD2/3.25 Also, TGF-b can initiate both a SMAD-dependent and a SMADindependent mitogen-activated protein kinase (MAPK) pathway.26

TG

INF-γ IL-2

6+

IL-1 IL-6 TGF-β

Response to intracellular pathogens

IL-

Naive CD4 T Cell

IL -4

IN Fγ

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Inflammation Autoimmune diseases

Figure 2 Developmental pathway and the relationship between Th17 cells and regulatory T cells. Th17, T helper 17 cells; Treg, regulatory T cells; IL, interleukin; TGF-b, transforming growth factor-b; FoxP3, Forkhead box P3; RORgt, retinoidrelated orphan receptor-g-t).


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and Th17 cells regarding their different immune regulation. These cells were found to play an important role in induction of immune tolerance. Forkhead box P3 (FoxP3) is involved in Treg-cell differentiation with a specific high expression.28 It is known that the generation of both FoxP3+ Treg cells and Th17 cells require TGF-b signaling. As FoxP3 is a transcription factor that is significantly expressed in CD4+ CD25+ Treg cells, its expression is crucial for their anergic phenotype and their suppression function.29,30 Therefore, a reciprocal relationship between Th17 and Treg development has been proposed. FoxP3+ Treg cells with sufficient TGF-b together with antigen presenting cells (APC) can support Th17 differentiation and apparently can undergo self-induced Th17-cell differentiation.31 To find out the exact mechanism, a fluorescent protein mark was used and it showed that FoxP3 sometimes co-expressed with retinoid-related orphan receptor-g-t (RORgt), a critical transcription factor required for Th17 differentiation. But actually the cells co-expressed with RORgt and FoxP3 have lower IL-17 production compared to that of cells expressing RORgt alone. These findings suggest that FoxP3 may inhibit Th17 differentiation by antagonizing RORgt function.32–35 This information indicates that the reciprocal relationship and regulation between Th17 and Treg cells remain complex and plastic. Although Th17 cells may induce autoimmunity while Treg cells inhibit autoimmune tissue injury, the interaction between Th17 and Treg cells will likely be further expanded in the future (Fig. 2).

Th17 cells and liver diseases Many researches have demonstrated the importance of Th17 cells in the pathogenesis of autoimmune inflammatory disease, such as experimental autoimmune encephalomyelitis (EAE)36 and arthritis37 in animal models. In more recent studies, it was shown that IL-17 also contributed to the formation of lupus-like diseases38 and colitis.39 Moreover, Th17 cells were also closely related to human autoimmune and inflammatory diseases. In clinical investigation of psoriasis,40,41 multiple sclerosis,42,43 systemic sclerosis,44 ankylosing spondylitis45 and juvenile idiopathic arthritis,46 a high level of IL-17 and other cytokines related to the Th17 pathway were found in patients’ serum and tissues. Nowadays, whether Th17 cells are involved in the pathogenesis of liver diseases and what kind of role they play attract more and more attention.



Th17 cells and liver autoimmunity As we know that Th17 cells have taken an important part in the pathogenesis of many organ-specific autoimmune diseases, and IL-17 has been identified as a key inflammatory cytokine involved in a number of autoimmune diseases. The role of Th17 cells in autoimmune liver diseases has caused extensive concern. Primary biliary cirrhosis (PBC) remains an enigmatic autoimmune liver disease featuring the presence of automitochondrial antibodies and damage to the small bile ducts, especially in women. Th17 cells in peripheral blood and liver tissues were found to be increased in PBC patients compared with that in normal controls.47–49 Also, IL-17, pro-Th17 cytokines, IL-6 and IL-23 were also found upregulated significantly both in gene expression and serum concentration in PBC patients compared with that in healthy controls.47 In IL-2Ra knockout (IL-2RaKO) mice (an animal model of human PBC)50–52 it was found that there was marked aggregation of IL-17-positive cells near the portal triad that is similar to the observation in PBC patients. What is more, compared to those from the spleen, CD4+ T cells isolated from liver tissues of the IL-2RaKO mice comprised a significantly higher percentage of Th17 cells. Investigations found that patients with PBC had a relative reduction of Treg cells compared with controls, suggesting the role Treg play in the loss of tolerance in PBC.53,54 It is proposed that increased Th17 cells and decreased Treg cells could be development of PBC in the IL-2RaKO mice,50 as Th17 cells are considered to induce autoimmunity injury and Treg cells inhibit autoimmune tissue injury.55 To sum up, the balance between Th17 cells and Treg cells in both number and function may play an important role in the pathogenesis and development of autoimmunity. It also provides a therapeutic opportunity for the treatment of autoimmune liver diseases by addressing the balance of Th17 and Treg cells. Autoimmune hepatitis (AIH), another autoimmune liver disease, in which Treg cells are defective numerically and functionally with a lower frequency,56–58 exhibits an increased frequency of IL-17-producing cells in liver tissues compared with healthy controls.48 All these suggested a key role of the liver micro-environment in Th17 induction in liver autoimmunity.

Infection and inflammation and Th17 cells T-helper 17 cells have been perceived as proinflammatory cells and directly bound up with infection and inflammation.59,60 Studies on acute hepatic injury


(AHI) patients showed that the serum IL-17 level was significantly higher than the normal controls, which suggested the usefulness of IL-17 in evaluating the severity of AHI.61 Cytokine IL-22 is also primarily expressed by Th17 CD4+ T cells and is highly upregulated during several chronic inflammatory diseases.62–64 Because IL-17 is upregulated in the lesions of patients with various chronic inflammatory diseases,40,41,65,66 it indicates that IL-22 and IL-17 may be likely to serve similar roles in vivo during inflammation. Moreover, it was found that IL-22 may play a protective role during acute liver inflammation.67 Later investigations showed that in the lectin concanavalin (ConA)-mediated acute liver inflammation model, IL-22 protected hepatocytes from the destructive effects of activated T cells, while IL-17 did not play an observable role in disease pathogenesis, which suggested that although IL-17 and IL-22 are co-expressed by inflammatory T cells, they may have distinct functions in the host inflammatory response.68 It was found that the percentage of circulating Th17 cells were significantly higher in the peripheral blood of chronic hepatitis B (CHB) patients than that in the control group, the same as in the liver tissues. Moreover, the Th17 cells increase correlated positively with the plasma viral load, serum alanine aminotransferase (ALT) levels and liver histological activity index, and the concentrations of Th17-associated cytokines including IL-17, IL-6 and IL-23 were also upregulated in CHB patients,69,70 which suggest that Th17-cell frequency is closely related to liver injury. It was also found that STAT3 inhibits T-cell-mediated hepatitis by regulating Th1 cytokine and IL-17.71 In addition, a similar phenomenon was found in hepatitis C virus (HCV) infection. It was reported that the serum IL-17 level and also the IL-17-positive cells accumulated markedly more in liver of HCV patients than that of control persons.48,49 Interleukin-17 was originally reported as a proinflammatory cytokine, that is not only essential for the development of inflammatory diseases, but also closely related to an infection leading to hepatic granulomas.72,73 What is more, IL-17 was reported to be involved in the infection of pathogens such as Klebsiella pneumoniae and Candida albicans.74,75 It has also been reported to have a similar effect in infection with intracellular bacteria Mycobacterium tuberculosis and Mycobacterium bovis.76,77 Lately, studies concerning Listeria monocytogenes demonstrated that IL-17 expressed in the liver of mice infected with L. monocytogenes at an early stage of infection. IL-17-deficient mice showed an aggravation of the protective response. It is shown that IL-17 is an important protective cytokine in the innate immu-


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nity in the liver, which was produced by g/d T cells at the early stage of L. monocytogenes infection.78

Alcoholic liver disease (ALD) Nowadays, ALD is attracting more and more attention because it has been found as a very important precursor of cirrhosis, and even a risk factor for cirrhosis-related deaths.79,80 A subset of ALD patients called alcoholic hepatitis (AH) may develop an acute and virulent form of inflammatory injury, which has a worse prognosis.81 Researchers have found that ALD involves dysregulation of both innate and adaptive immunity,82 and shares some features with autoimmune diseases.83–85 Many different cell types including T lymphocytes, monocytes and neutrophils are primed in ALD. Recently, investigations found that patients with ALD have a high plasma level of IL-17, and Th17 cells were also found to be accumulated in the livers of patients with ALD, which was closely related with biological hepatocellular damage. In addition, no matter whether ALD patients have AH or not, IL-17 cell infiltration is correlated to fibrosis score.86 All this suggests that the IL-17 pathway plays a very important role in human ALD, and that Th17 cells may contribute to the pathogenesis of ALD.

Liver carcinoma and transplantation of Th17 cells Hepatocellular carcinoma (HCC) is usually evolved from inflamed fibrotic and/or cirrhotic liver with extensive lymphocyte infiltration due to chronic viral infection. Therefore, the immune status at the tumor site may greatly affect the biological behavior of HCC.87,88 Many studies suggested that IL-17 promotes tumor growth by increasing angiogenesis and intratumoral infiltration of phagocytes in mice which are closely associated with the progress and prognosis of tumor.89,90 Moreover, in both peripheral blood and tumor tissues from cancer patients an increase in IL-17-producing cells has been found.91 It was also demonstrated that Th17 cells were enriched in tumors of HCC patients, and that IL-17-producing cells could serve as a potential prognosis marker and a novel therapeutic target for patients with HCC.92 It has been shown that there was an association between IL-17 secreted from Th17 cells and acute renal allograft rejection.93 In the model of heart transplantation, inhibition of IL-17 activity reduced inflammatory infiltrates and delayed acute allograft rejection.94 During the acute rejection after lung transplantation, IL-17 has also been found at a higher expression in the reject tissues.95 Recently, studies on the requirement of dialysis after liver transplant receptors suggested that the dys-


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regulated expression of Th1, Th2 and Th17 cells was closely related to the susceptibility infections in highrisk liver transplant recipients.96 Additionally, in the study on liver transplantation, the serum levels of IL-23 and IL-17 in the transplant group were higher than that in the control group during the entire postoperative period, indicating that IL-23 and IL-17 are upregulated during acute hepatic rejection.97

FORWARD

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LTHOUGH THE RESEARCHES on Th17 cells have made some progress, there are still some questions that need to be further clarified, such as the interaction between Th17 cells and other subsets of T cells, especially Th1 cells, and the concrete mechanism by which Th17 cells act in liver diseases, especially in autoimmune liver diseases and hepatic rejection. It is believed that the continuous understanding of Th17 cell differentiation and regulation, and further studies of its physiological and pathological functions, will provide us with new ideas targeting autoimmunity, inflammation and carcinoma.

ACKNOWLEDGEMENTS*

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HIS WORK WAS supported by grants from Zhejiang Provincial Natural Science Foundation of China (Y207464), Scientific Research Foundation of Wenzhou, Zhejiang Province, China (H20090014, Y20090269), Research Foundation of Education Bureau of Zhejiang Province (Y201009942), and Health Bureau of Zhejiang Province (2010KYB070).


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