• immunotherapy
• innate and adaptive immunity
• liver diseases
• γδT cells

• Humans
• Liver Diseases/immunology
• Liver Diseases/therapy
• Liver Diseases/pathology
• Liver Diseases/metabolism
• Animals
• Receptors, Antigen, T-Cell, gamma-delta/metabolism
• Receptors, Antigen, T-Cell, gamma-delta/immunology
• T-Lymphocyte Subsets/immunology
• T-Lymphocyte Subsets/metabolism

• clearance of HBsAg
• hepatitis B
• immune checkpoint inhibitors (ICIs)
• immune-mediated liver injury caused by checkpoint inhibitors (ILICI)
• liver failure

• NKG2A receptor
• Vδ2 T-cell
• hepatitis virus
• hepatocellular carcinoma
• human leukocyte antigen
• natural killer cells

• [no grant number provided] Italian Ministry of Health (Ricerca Corrente)

• Antiviral
• Functional Cure
• Screening
• Treatment

• Humans
• Hepatitis B Surface Antigens/genetics
• Antiviral Agents/therapeutic use
• Antiviral Agents/pharmacology
• Hepatitis B/drug therapy
• Hepatitis B virus/genetics
• Hepatitis B, Chronic/diagnosis
• Hepatitis B, Chronic/drug therapy
• Hepatitis B, Chronic/epidemiology
• DNA, Circular
• Liver Neoplasms/prevention & control
• Liver Neoplasms/drug therapy
• DNA, Viral
• Virus Replication

• ZIA DK054517 Intramural NIH HHS

• prognostic markers
• diagnostic markers

• Humans
• Hepatitis B virus
• Hepatitis B, Chronic/diagnosis
• Hepatitis B, Chronic/drug therapy
• Antiviral Agents/therapeutic use
• Virus Replication
• Biomarkers
• Disease Progression
• Hepatitis B/diagnosis
• Hepatitis B/drug therapy

• 26603 Cancer Research UK
• 26813 Cancer Research UK
• G0901374 Medical Research Council
• R01 DK044533 NIDDK NIH HHS

• the National Science Foundation of China
• Clinical Research Startup Program of Southern Medical University by High-level University Construction Funding of Guangdong Provincial Department of Education
• Clinical Research Program of Nanfang Hospital, Southern Medical University
• The funding sources did not have any influence on the study design, data collection, analysis and interpretation of the data, writing of the manuscript, or decision to submit for publication

• CLL
• Vδ1
• Vδ2
• Vδ3
• chronic lymphocytic leukaemia
• cytotoxicity
• γδ T

• B-Lymphocytes
• Humans
• Immunotherapy
• Leukemia, Lymphocytic, Chronic, B-Cell/therapy
• Lymphocyte Count

• 2019/35/N/NZ6/02973 National Science Center
• PBsd 161 Medical University of Lublin

Gamma delta (γδ) T cells play a key role in the innate immune response and serve as the first line of defense against infection and tumors. These cells are defined as tissue-resident lymphocytes in skin, lung, and intestinal mucosa. They are also relatively abundant in the liver; however, little is known about the residency of hepatic γδT cells. By comparing the phenotype of murine γδT cells in liver, spleen, thymus, and small intestine, a CXCR3⁺CXCR6⁺ γδT-cell subset with tissue-resident characteristics was found in liver tissue from embryos through adults. Liver sinusoidal endothelial cells mediated retention of CXCR3⁺CXCR6⁺ γδT cells through the interactions between CXCR3 and CXCR6 and their chemokines. During acute HBV infection, CXCR3⁺CXCR6⁺ γδT cells produced high levels of IFN-γ and adoptive transfer of CXCR3⁺CXCR6⁺ γδT cells into acute HBV-infected TCRδ^−/− mice leading to lower HBsAg and HBeAg expression. It is suggested that liver resident CXCR3⁺CXCR6⁺ γδT cells play a protective role during acute HBV infection. Strategies aimed at expanding and activating liver resident CXCR3⁺CXCR6⁺ γδT cells both in vivo or in vitro have great prospects for use in immunotherapy that specifically targets acute HBV infection.

• Adoptive Transfer/methods
• Animals
• Chemokines/metabolism
• Hepatitis B/metabolism
• Hepatitis B virus/pathogenicity
• Hepatocytes/metabolism
• Hepatocytes/virology
• Intestine, Small/metabolism
• Intestine, Small/virology
• Liver/metabolism
• Liver/virology
• Male
• Mice
• Mice, Inbred BALB C
• Mice, Inbred C57BL
• Mice, Nude
• Receptors, Antigen, T-Cell, gamma-delta/metabolism
• Receptors, CXCR3/metabolism
• Receptors, CXCR6/metabolism
• Spleen/metabolism
• Spleen/virology
• T-Lymphocytes/metabolism
• T-Lymphocytes/virology
• Thymus Gland/metabolism
• Thymus Gland/virology

γδ T cells are activated in viral, bacterial and parasitic infections. Among viruses that promote γδ T cell mobilisation in humans, herpes viruses (HHVs) occupy a particular place since they infect the majority of the human population and persist indefinitely in the organism in a latent state. Thus, other infections should, in most instances, be considered co-infections, and the reactivation of HHV is a serious confounding factor in attributing γδ T cell alterations to a particular pathogen in human diseases. We review here the literature data on γδ T cell mobilisation in HHV infections and co-infections, and discuss the possible contribution of HHVs to γδ alterations observed in various infectious settings. As multiple infections seemingly mobilise overlapping γδ subsets, we also address the concept of possible cross-protection.

• CMV
• HHV
• co-infections
• gamma delta T cells
• herpes virus
• lymphocytes

• Adaptive Immunity
• Coinfection
• Herpesviridae/immunology
• Herpesviridae Infections/complications
• Herpesviridae Infections/immunology
• Herpesviridae Infections/virology
• Humans
• Immunity, Innate
• Intraepithelial Lymphocytes/immunology
• Intraepithelial Lymphocytes/virology
• Lymphocytes/immunology
• Malaria/complications
• Mycobacterium Infections/complications
• Virus Diseases/complications
• Virus Diseases/virology
• Virus Latency

• chronic hepatitis B
• direct-acting antivirals
• functional cure
• hepatitis B virus
• immunotherapy

• Bacille Calmette-Guérin vaccine
• COVID-19
• antiviral
• gamma delta T cell
• innate immunity
• non-specific immunity
• trained immunity
• vaccine

• Animals
• BCG Vaccine/economics
• BCG Vaccine/pharmacology
• BCG Vaccine/therapeutic use
• COVID-19/prevention & control
• Costs and Cost Analysis
• Humans
• SARS-CoV-2
• T-Lymphocyte Subsets/drug effects
• T-Lymphocyte Subsets/immunology
• Vaccination/economics

Hepatocellular carcinoma (HCC) develops almost entirely in the presence of chronic inflammation. Chronic hepatitis B virus (HBV) infection with recurrent immune-mediated liver damage ultimately leads to cirrhosis and HCC. It is widely accepted that HBV infection induces the dysfunction of the innate and adaptive immune responses that engage various immune cells. Natural killer (NK) cells are associated with early antiviral and antitumor properties. On the other hand, inflammatory cells release various cytokines and chemokines that may promote HCC tumorigenesis. Moreover, immunosuppressive cells such as regulatory T cells (Treg) and myeloid-derived suppressive cells play a critical role in hepatocarcinogenesis. HBV-specific CD8+ T cells have been identified as pivotal players in antiviral responses, whilst extremely activated CD8+ T cells induce enormous inflammatory responses, and chronic inflammation can facilitate hepatocarcinogenesis. Controlling and maintaining the balance in the immune system is an important aspect in the management of HBV-related HCC. We conducted a review of the current knowledge on the immunopathogenesis of HBV-induced inflammation and the role of such immune activation in the tumorigenesis of HCC based on the recent studies on innate and adaptive immune cell dysfunction in HBV-related HCC.

• adaptive immunity
• hepatitis B virus
• hepatocellular carcinoma
• immune balance
• immune cells
• innate immunity

• CD8-Positive T-Lymphocytes/immunology
• CD8-Positive T-Lymphocytes/pathology
• Carcinogenesis/immunology
• Carcinogenesis/pathology
• Carcinoma, Hepatocellular/immunology
• Carcinoma, Hepatocellular/pathology
• Carcinoma, Hepatocellular/virology
• Hepatitis B virus/immunology
• Hepatitis B, Chronic/immunology
• Hepatitis B, Chronic/pathology
• Humans
• Liver Neoplasms/immunology
• Liver Neoplasms/pathology
• Liver Neoplasms/virology
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/pathology

• HR21C1003, HI19C0872 Korea Health Industry Development Institute

Although millions of patients have clinically recovered from COVID-19, little is known about the immune status of lymphocytes in these individuals. In this study, the peripheral blood mononuclear cells of a clinically recovered (CR) cohort were comparatively analyzed with those of an age- and sex-matched healthy donor cohort. We found that CD8⁺ T cells in the CR cohort had higher numbers of effector T cells and effector memory T cells but lower Tc1 (IFN-γ⁺), Tc2 (IL-4⁺), and Tc17 (IL-17A⁺) cell frequencies. The CD4⁺ T cells of the CR cohort were decreased in frequency, especially the central memory T cell subset. Moreover, CD4⁺ T cells in the CR cohort showed lower programmed cell death protein 1 (PD-1) expression and had lower frequencies of Th1 (IFN-γ⁺), Th2 (IL-4⁺), Th17 (IL-17A⁺), and circulating follicular helper T (CXCR5⁺PD-1⁺) cells. Accordingly, the proportion of isotype-switched memory B cells (IgM⁻CD20^hi) among B cells in the CR cohort showed a significantly lower proportion, although the level of the activation marker CD71 was elevated. For CD3⁻HLA-DR⁻ lymphocytes in the CR cohort, in addition to lower levels of IFN-γ, granzyme B and T-bet, the correlation between T-bet and IFN-γ was not observed. Additionally, by taking into account the number of days after discharge, all the phenotypes associated with reduced function did not show a tendency toward recovery within 4‒11 weeks. The remarkable phenotypic alterations in lymphocytes in the CR cohort suggest that  severe acute respiratory syndrome coronavirus 2 infection profoundly affects lymphocytes and potentially results in dysfunction even after clinical recovery.

• COVID-19
• lymphocyte subsets
• phenotypic alteration
• potential dysfunction
• recovered individuals

• chronic hepatitis B
• exhaustion
• γδ T cells

Studies of human hepatitis B virus (HBV) immune pathogenesis are hampered by limited access to liver tissues and technologies for detailed analyses. Here, utilizing imaging mass cytometry (IMC) to simultaneously detect 30 immune, viral, and structural markers in liver biopsies from patients with hepatitis B e antigen⁺ (HBeAg⁺) chronic hepatitis B, we provide potentially novel comprehensive visualization, quantitation, and phenotypic characterizations of hepatic adaptive and innate immune subsets that correlated with hepatocellular injury, histological fibrosis, and age. We further show marked correlations between adaptive and innate immune cell frequencies and phenotype, highlighting complex immune interactions within the hepatic microenvironment with relevance to HBV pathogenesis.

• Adaptive immunity
• Fibrosis
• Hepatology
• Infectious disease
• Innate immunity

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are primary risk factors for a wide spectrum of liver diseases that severely affect human health. The liver is an immunological organ that has an abundance of immune cells. Thus, various innate or adaptive immune cells are involved in the progression of HBV or HCV infection. Among those cells, a unique kind of immune cell, the γδ T cell, contributes to promoting or inhibiting the progression of liver diseases. To reveal the diverse roles of γδ T cells in HBV or HCV infection, the properties and functions of these cells in human and mouse models are analyzed. Here, we briefly describe the characteristics and functions of γδ T cells subsets in liver diseases. Then, we fully discuss the diverse roles of γδ T cells in the progression of HBV or HCV infection, including stages of acute infection, chronic infection, liver cirrhosis, and hepatocellular carcinoma. Finally, the functions and existing problems of γδ T cells in HBV or HCV infection are summarized. A better understanding of the function of γδ T cells during the progression of HBV and HCV infection will be helpful for the treatment of virus infection.

• cytokines
• hepatitis B virus
• hepatitis C virus
• progression
• γδ T cells

• butyrophilins
• innate immunity
• phosphoantigens
• unconventional T cells
• γδ T cells

• CD8(+) cells
• Immunosuppressive microenvironment
• Immunotherapy
• Th cells
• Tregs
• γδ T cells

• immune landscape
• mass cytometry
• proteome
• single-cell

• 81871448 National Natural Science Foundation of China
• 2017SHZDZX01 Shanghai Municipal Science and Technology
• ZXWF082101 Shanghai Municipal Education Commission
• National Natural Science Foundation of China
• Shanghai Municipal Education Commission

The molecular pathogenesis of liver cancer remains unclear; some ncRNAs have been considered as potential drug targets for cancer treatment. LncRNA PSMG3‑AS1 has been reported to promote breast cancer, while its role in hepatocellular carcinoma (HCC) is unknown.

Bioinformatics analysis was conducted to investigate the relationship between miR-143-3p and PSMG3-AS1. RT-qPCR was used to detect the expression levels of miR-143-3p and PSMG3-AS1 and the correlation between them in HCC. The survival curve was used to analyze the effect of PSMG3-AS1 on the prognosis of liver cancer. RT-qPCR was used to detect the effect of different concentration gradients of miR-143-3p on PSMG3-AS1. CCK8 and clone formation experiments were used to examine the role of miR-143-3p and PSMG3-AS1 in regulating the proliferation of SNU-182 and SNU-398 cells.

Our preliminary bioinformatics analysis showed that miR-143-3p can target PSMG3-AS1. We, therefore, analyzed the interaction between PSMG3-AS1 and miR-143-3p in HCC. We found that PSMG3-AS1 was upregulated, while miR-143-3p was downregulated in HCC. The expression levels of PSMG3‑AS1 and miR-143-3p were closely and inversely correlated with each other. High expression levels of PSMG3‑AS1 predicted poor survival. In HCC cells, overexpression of PSMG3-AS1 led to increased proliferation rates. Overexpression of miR-143-3p played an opposite role and reversed the effect of overexpression of PSMG3‑AS1.

miR-143-3p may target PSMG3‑AS1 to inhibit the proliferation of HCC cells.

• hepatocellular carcinoma
• lncRNA PSMG3-AS1
• miR-143-3p
• proliferation

A great effort of research has been devoted in the last few years to developing new anti-HBV therapies of finite duration that also provide effective sustained control of virus replication and antigen production. Among the potential therapeutic strategies, immune-modulation represents a promising option to cure HBV infection and the adaptive immune response is a rational target for novel therapeutic interventions, in consideration of the key role played by T cells in the control of virus infections. HBV-specific T cells are severely dysfunctional in chronic HBV infection as a result of several inhibitory mechanisms which are simultaneously active within the chronically inflamed liver. Indeed, the liver is a tolerogenic organ harboring different non-parenchymal cell populations which can serve as antigen presenting cells (APC) but are poorly efficient in effector T cell priming, with propensity to induce T cell tolerance rather than T cell activation, because of a poor expression of co-stimulatory molecules, up-regulation of the co-inhibitory ligands PD-L1 and PD-L2 upon IFN stimulation, and production of immune regulatory cytokines, such as IL10 and TGF-β. They include resident dendritic cells (DCs), comprising myeloid and plasmacytoid DCs, liver sinusoidal endothelial cells (LSECs), Kupffer cells (KCs), hepatic stellate cells (HSCs) as well as the hepatocytes themselves. Additional regulatory mechanisms which contribute to T cell attrition in the chronically infected liver are the high levels of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines, the up-regulation of inhibitory checkpoint receptor/ligand pairs, the expansion of regulatory cells, such as CD4+FOXp3+ Treg cells, myeloid-derived suppressor cells and NK cells. This review will deal with the interactions between immune cells and liver environment discussing the different mechanisms which contribute to T cell dysfunction in chronic hepatitis B, some of which are specifically activated in HBV infection and others which are instead common to chronic inflammatory liver diseases in general. Therapeutic interventions targeting dysregulated pathways and cellular functions will be also delineated.

• T cell exhaustion
• chronic HBV infection
• immune-therapy
• immunoregulatory mechanisms
• liver environment

Chronic hepatitis B virus (HBV) infection is one of the high-risk factors for human HCC. Despite the integration of virus DNA and the oncoprotein HBx, chronic necroinflammation and hepatocellular regeneration account for hepatocarcinogenesis. As a non-cytopathic virus, HBV is extensively recognized to mediate chronic liver damage through abnormal immune attack. However, the mechanisms driving HBV infection to HCC are poorly understood. During chronic HBV infection in humans, the adaptive immunity changes from immune tolerance to progressive immune activation, inactivation, reactivation and exhaustion, all of which may be the immune pathogenic factors for the development of HCC. Recently, the immunopathogenic mechanisms were described in mouse HBV-induced HCC models, which is absolutely dependent on the presence of HBV-specific T cell response and NK cell-derived IFN-γ, findings which are consistent with the observations from CHB and HCC patients. In this review, we summarize recent research progression on the HBV-specific CD8⁺ T cells, and also CD4⁺ T cells, B cells and non-specific immune cells and molecules underlying chronic HBV infection and eventual HCC development to demonstrate the pathogenesis of HBV-induced immune imbalance. Based on the progression, we discussed the potential of immune-based therapies and their challenges in the treatment of HBV-related HCC, including the checkpoint inhibition, genetically modified T cell transfer, therapeutic vaccines and metabolic modulation.

• HBV
• HCC
• adaptive immunity
• immune dysfunction
• innate immunity