Interleukin-17-producing CD4+ T cells increase with severity of liver damage in patients with chronic hepatitis B

Zhang, Jiyuan; Zhang, Zheng; Lin, Fang‐Yue; Zou, Zhengsheng; Xu, Ruonan; Jin, Lei; Fu, Junliang; Shi, Feng; Shi, Ming; Wang, Huifen; Wang, Fusheng

doi:10.1002/hep.23273

Cited by 344 publications

(396 citation statements)

References 37 publications

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“…IL-17A production triggers several inflammatory conditions (26) and has been implicated in the establishment of liver fibrosis (42) and in the pathogenesis of alcoholic, autoimmune, and hepatitis B virus-or hepatitis C virus-related hepatitis (42)(43)(44)(45). Importantly, in all these chronic inflammatory conditions, IL-17-producing CD4 + T (Th17) cells were reported to be the major source of IL-17A in the liver, with few reports describing IL-17A-producing CD161 + CD8 + T cells (11,45).…”

Section: Discussionmentioning

confidence: 99%

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

Tang

Tan

et al. 2013

The Journal of Immunology

301

393

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Human mucosal-associated invariant T (MAIT) cells are a T cell population characterized by the expression of a semi-invariant TCR capable of recognizing bacterial products in the context of MR1. MAIT cells are enriched in the human liver, which is constantly exposed to bacterial products from the intestine. Whether this specific parenchymal localization influences their function remains unknown. We analyzed MAIT cells resident in the vascular bed of livers and showed that they represented the majority of T cells expressing NK markers and the dominant IL-17A+ T cell subset in the human liver sinusoids. In comparison with MAIT cells purified from peripheral blood, intrasinusoidal MAIT cells expressed markers of T cell activation; however, TCR-mediated cytokine production was equally suppressed in both circulating and intrasinusoidal MAIT cells. MAIT cells also expressed high levels of IL-7R, and we showed that IL-7, a cytokine produced by hepatocytes during inflammation, regulated TCR-mediated activation of MAIT cells, licensing them to dramatically increase Th1 cytokines and IL-17A production. Our quantitative and functional data indicate that MAIT cells are a specialized cell population highly adapted to exert their immune functions in the vascular network of the liver.

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Section: Discussionmentioning

confidence: 99%

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

Tang

Tan

et al. 2013

The Journal of Immunology

301

393

View full text Add to dashboard Cite

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“…Paraffin-embedded, formalin-fixed liver tissue sections (5 μm) were incubated with anti-IL-33 antibody or anti-MPO antibody overnight at 4°C after blocking endogenous peroxidase activity with 0.3% H 2 O 2 . 3-Amino-9-ethylcarbazole (red color) was used as the substrate, followed by counterstaining with hematoxylin, according to previously described protocols (Zhang et al 2010). The percentage of IL-33 positive cells was analyzed semi-quantitatively based on the red-positive area under lower-power fields (200×) with the software, IPP6.0.…”

Section: Immunohistochemical Stainingmentioning

confidence: 99%

Interleukin-33 Promotes Disease Progression in Patients with Primary Biliary Cirrhosis

Sun

Zhang

et al. 2014

Tohoku J. Exp. Med.

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Primary biliary cirrhosis (PBC) is a progressive autoimmune liver disease that can cause a series of complications, including cirrhosis, liver failure and hepatocellular carcinoma. Interleukin-33 (IL-33) is expressed in various non-hematopoietic cells and a certain population of immune cells, and exerts its biological effects by binding to the specific receptor, suppression of tumorigenicity 2 (ST2). A soluble form of ST2 (sST2) has been postulated to act as a decoy receptor for IL-33. In this study, we aimed to investigate the role of IL-33 in the pathogenesis of PBC. The study included 20 healthy controls and 68 patients with PBC. We thus found the increased serum IL-33 levels in PBC patients. Its elevated levels were positively correlated with serum alkaline phosphatase levels (a key parameter for the definition of PBC) and with Child-Pugh scores, which were used to determine the prognosis of liver cirrhosis. Moreover, the serum concentrations of sST2 were significantly higher in PBC patients compared with healthy subjects, irrespective of the disease severity. Importantly, the cells that express IL-33 and/or myeloperoxidase (a marker for neutrophils) were accumulated in the livers of PBC patients, and their number increased with the severity of liver lesions. Lastly, in vitro chemotaxis assays revealed that IL-33 enhanced the migration of neutrophils. These data suggest that IL-33 may affect the progress of PBC by recruiting neutrophils to the liver. This expanded knowledge of IL-33 in PBC patients is important for developing therapeutic strategies (e.g., neutralization of IL-33), selecting optimal clinical management, and predicting prognosis.

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“…The peripheral cells were analyzed using protocols previously described by our team with minor modification [27][28][29][30].…”

Section: Phenotypic Analysismentioning

confidence: 99%

Upregulation of OX40 ligand on monocytes contributes to early virological control in patients with chronic hepatitis C

Zhang

Yang

et al. 2013

Eur J Immunol

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Dysfunctional hepatitis C virus (HCV) specific CD4 + T cells are known to contribute to inadequate adaptive immunity in chronic hepatitis C (CHC), although the underlying mechanisms remain largely undefined. In this study, OX40 ligand (OX40L) expression was investigated in 41 treatment-naïve CHC patients, 20 sustained virological responders and 36 healthy subjects. We observed that OX40L expression was significantly upregulated in peripheral monocytes in CHC patients compared with sustained virological responders and healthy subjects. OX40L upregulation correlated significantly with plasma viral load rather than serum alanine aminotransaminase levels. Furthermore, longitudinal analyses indicated that upregulated OX40L expression on monocytes is closely associated with rapid or early virological responses in patients receiving pegylated IFN-α/ ribavirin treatment. In vitro, HCV core antigen strongly stimulated monocyte expression of OX40L and blockade of TLR2 signaling significantly downregulated OX40L expression. More importantly, elevated OX40L expression was also shown to be closely associated with elevation of the HCV-specific CD4 + T-cell response and in vitro blockade of OX40L expressed on monocytes led to impaired CD4 + T-cell function. These findings, therefore, implicate OX40L expression can be used as a marker to evaluate antiviral treatment efficacy and extend the notion that enhancement of OX40L expression could be a good way for immunotherapy in CHC patients. Keywords: Chronic hepatitis C (HCV) r Monocyte r OX40 ligandAdditional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Dr. Fu-Sheng Wang e-mail: fswang302@163.com * These authors contributed equally to this study. 1954 Ji-Yuan Zhang et al. Eur. J. Immunol. 2013. 43: 1953-1962 Introduction The hepatitis C virus (HCV) leads to chronic infection and viral persistence in 85% of infected individuals and an estimated 180 million people are infected worldwide [1,2]. In China, HCV has gradually become a major public health problem, with anti-HCV prevalence in the general population at approximately 3.2%. This level increases with age, thus implicating age as an individual risk factor for HCV infection [3]. Following exposure to HCV, CD4 + and CD8 + T-cell responses to HCV are stronger in patients exhibiting spontaneous resolution of HCV infection, whereas the decay of virus-specific T cells, manifested as functional impairment of proliferative and lytic capacity and exhausted cytokine production, is observed in patients developing chronicity of HCV infection. Furthermore, during acute self-limited HCV infections, HCV-specific CD4 + T cells have been shown to play a crucial role in the maintenance of an effective ongoing CD8 + T-cell response. In contrast, the impaired capacity of HCV-specific CD4 + T cells is thought to be one of the key mechanisms responsible for the compromised protective CD8 + T-cell responses [4,5].Expression of OX40 ligand (OX40L), a TNF family member, has been...

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Interleukin-17-producing CD4+ T cells increase with severity of liver damage in patients with chronic hepatitis B

Cited by 344 publications

References 37 publications

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

IL-7 Licenses Activation of Human Liver Intrasinusoidal Mucosal-Associated Invariant T Cells

Interleukin-33 Promotes Disease Progression in Patients with Primary Biliary Cirrhosis

Upregulation of OX40 ligand on monocytes contributes to early virological control in patients with chronic hepatitis C

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