Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV

Fang, Zhong; Zhang, Yi; Zhu, Zhiming; Wang, Cong; Hu, Yao; Peng, Xinjun; Zhang, Dandan; Jun, Zhao; Shi, Bisheng; Shen, Zhongliang; Wu, Min; Xu, Chunhua; Chen, Jieliang; Zhou, Xiaohui; Xie, Youhua; Yu, Hui; Zhang, Xiaonan; Li, Jianhua; Hu, Yunwen; Kozlowski, Maya; Bertoletti, Antonio; Yuan, Zhenghong

doi:10.1084/jem.20211838

Cited by 10 publications

(6 citation statements)

References 65 publications

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“…Previous studies demonstrated that HBV-specific CD4+/CD8+ T cell dysfunction or depletion plays a vital role in persistent infection caused by HBV ( Fisicaro et al, 2017 ; Polaris Observatory Collaborators, 2018 ; Yong et al, 2018 ; Pan et al, 2020 ; Huang et al, 2021 ; Fang et al, 2022 ; Li et al, 2022 ; Zhang et al, 2022 ). In a recent study by Zhang et al, the single-cell immune sequences of 0.243 million cells from 46 pairs of peripheral blood and liver samples of 23 patients were analyzed, and the dynamic alterations of T cell depletion after HBV infection were profiled ( Zhang et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…Since the ALT level is not always indicative of inflammation in the liver, patients with normal ALT levels can present inflammation and fibrosis on liver biopsy. Thus, ALT is used as a substitute for liver inflammation when liver histology is a failure ( Wu et al, 2019 , 2020 ; Fang et al, 2022 ). But the challenge in defining the ULN (upper limits of normal) of ALT is the difficulty of including totally healthy subjects without liver diseases, especially MAFLD (Metabolic-Associated Fatty Liver Disease), the leading cause of liver disease worldwide ( Tampi et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Current treatment of chronic hepatitis B: Clinical aspects and future directions

et al. 2022

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Hepatitis B virus (HBV) infection is a public health threat worldwide, and there is no direct treatment yet available. In the event of infection, patients may present liver cirrhosis and cancer, which threaten the patients’ health globally, especially in the Asia-Pacific region and China. In 2019, Chinese hepatopathologists updated the 2015 Guidelines for the Prevention and Treatment of Chronic Hepatitis B as the clinical reference. The other versions formulated by the American Association for the Study of Liver Diseases (2018 AASLD guidelines) (AASLD, 2018), European Association for the Study of the Liver (2017 EASL guidelines) (EASL, 2017), and Asian-Pacific Association for the Study of the Liver (2015 APASL guidelines) (APASL, 2015) also provide clinical guidance. However, there are still some issues that need to be addressed. In the present study, the following aspects will be introduced successively: (1) Who should be treated in the general population according to the guidelines; (2) Treatment of specific populations infected with HBV; (3) Controversial issues in clinical practice; (4) Perspective.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Current treatment of chronic hepatitis B: Clinical aspects and future directions

et al. 2022

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“…In-vitro treatment of PBMC with HBeAg induces IDO expressing M-MDSCs which inhibit CD4 + and CD8 + T cell proliferation and IFN-γ production ( 156 ) Tregs can be induced by MDSCs in HBV infection in an IL-10 and TGF-β dependent process ( 155 ). In a mouse model, chemokine receptor CCR9 in M-MDSCs is induced by HBsAg via ERK/IL-6 pathway, and CCR9-CCL25 interaction mediates Gr1 + Ly6C high Ly6G - M-MDSCs homing to the thymus, where HBsAg-specific CD8 + CD4 - T cells are killed by NOX1-expressing M-MDSCs ( 162 ). Another HBV-specific mechanism involves impaired CCR5-CCL5 interaction by TGF-β released from MDSCs, which affects the migration of HBV-specific T cells to the liver ( 152 , 163 , 164 ).…”

Section: Oncogenic Virusesmentioning

confidence: 99%

Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis

2023

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Myeloid derived suppressor cells (MDSCs) are a heterogenous population of myeloid cells derived from monocyte and granulocyte precursors. They are pathologically expanded in conditions of ongoing inflammation where they function to suppress both innate and adaptive immunity. They are subdivided into three distinct subsets: monocytic (M-) MDSC, polymorphonuclear (or neutrophilic) (PMN-) MDSC and early-stage (e-) MDSC that may exhibit differential function in different pathological scenarios. However, in cancer they are associated with inhibition of the anti-tumour immune response and are universally associated with a poor prognosis. Seven human viruses classified as Group I carcinogenic agents are jointly responsible for nearly one fifth of all human cancers. These viruses represent a large diversity of species, including DNA, RNA and retroviridae. They include the human gammaherpesviruses (Epstein Barr virus (EBV) and Kaposi’s Sarcoma-Associated Herpesvirus (KSHV), members of the high-risk human papillomaviruses (HPVs), hepatitis B and C (HBV, HCV), Human T cell leukaemia virus (HTLV-1) and Merkel cell polyomavirus (MCPyV). Each of these viruses encode an array of different oncogenes that perturb numerous cellular pathways that ultimately, over time, lead to cancer. A prerequisite for oncogenesis is therefore establishment of chronic infection whereby the virus persists in the host cells without being eradicated by the antiviral immune response. Although some of the viruses can directly modulate the immune response to enable persistence, a growing body of evidence suggests the immune microenvironment is modulated by expansions of MDSCs, driven by viral persistence and oncogenesis. It is likely these MDSCs play a role in loss of immune recognition and function and it is therefore essential to understand their phenotype and function, particularly given the increasing importance of immunotherapy in the modern arsenal of anti-cancer therapies. This review will discuss the role of MDSCs in viral oncogenesis. In particular we will focus upon the mechanisms thought to drive the MDSC expansions, the subsets expanded and their impact upon the immune microenvironment. Importantly we will explore how MDSCs may modulate current immunotherapies and their impact upon the success of future immune-based therapies.

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“…For patients with viral load>107 copies/ml, it is difficult to detect CD8 + T cells, whose deletion mechanism is still unclear, but it has been reported that it may be related in part to increased apoptosis of CD8 + T cells ( 24 ). A recent research has explored the causes and found that HBV can eliminate immature HBsAg-specific T cells in the thymus through monocytic myeloid derived suppressor cells (mMDSCs), thus forming an HBV-specific T-cell tolerance environment ( 25 ).…”

Section: Persistent Hbv Infection and Host Immune Responsementioning

confidence: 99%

Hepatitis B functional cure and immune response

2022

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Hepatitis B virus (HBV) is a hepatotropic virus, which damage to hepatocytes is not direct, but through the immune system. HBV specific CD4+ T cells can induce HBV specific B cells and CD8+ T cells. HBV specific B cells produce antibodies to control HBV infection, while HBV specific CD8+ T cells destroy infected hepatocytes. One of the reasons for the chronicity of HBV infection is that it cannot effectively activate adoptive immunity and the function of virus specific immune cells is exhausted. Among them, virus antigens (including HBV surface antigen, e antigen, core antigen, etc.) can inhibit the function of immune cells and induce immune tolerance. Long term nucleos(t)ide analogues (NAs) treatment and inactive HBsAg carriers with low HBsAg level may “wake up” immune cells with abnormal function due to the decrease of viral antigen level in blood and liver, and the specific immune function of HBV will recover to a certain extent, thus becoming the “dominant population” for functional cure. In turn, the functional cure will further promote the recovery of HBV specific immune function, which is also the theoretical basis for complete cure of hepatitis B. In the future, the complete cure of chronic HBV infection must be the combination of three drugs: inhibiting virus replication, reducing surface antigen levels and specific immune regulation, among which specific immunotherapy is indispensable. Here we review the relationship, mechanism and clinical significance between the cure of hepatitis B and immune system.

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Monocytic MDSCs homing to thymus contribute to age-related CD8+ T cell tolerance of HBV

Cited by 10 publications

References 65 publications

Current treatment of chronic hepatitis B: Clinical aspects and future directions

Current treatment of chronic hepatitis B: Clinical aspects and future directions

Deciphering the roles of myeloid derived suppressor cells in viral oncogenesis

Hepatitis B functional cure and immune response

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