More than 250 million people are living with chronic hepatitis B despite the availability of highly effective vaccines and oral antivirals. Although innate and adaptive immune cells play crucial roles in controlling hepatitis B virus (HBV) infection, they are also accountable for inflammation and subsequently cause liver pathologies. During the initial phase of HBV infection, innate immunity is triggered leading to antiviral cytokines production, followed by activation and intrahepatic recruitment of the adaptive immune system resulting in successful virus elimination. In chronic HBV infection, significant alterations in both innate and adaptive immunity including expansion of regulatory cells, overexpression of co-inhibitory receptors, presence of abundant inflammatory mediators, and modifications in immune cell derived exosome release and function occurs, which overpower antiviral response leading to persistent viral infection and subsequent immune pathologies associated with disease progression towards fibrosis, cirrhosis, and hepatocellular carcinoma. In this review, we discuss the current knowledge of innate and adaptive immune cells transformations that are associated with immunopathogenesis and disease outcome in CHB patients.

Immunopathology of Chronic Hepatitis B Infection: Role of Innate and Adaptive Immune Response in Disease Progression

Members of the interleukin 12 (IL-12) family have been known to be inflammatory factors since their discovery. The IL-12 family consists of IL-12, IL-23, IL-27, IL-35, and a new member, IL-39, which has recently been identified and has not yet been studied extensively. Current literature has described the mechanisms of immunity of these cytokines and potential uses for therapy and medical cures. IL-12 was found first and is effective in combatting a wide range of naturally occurring viral infections through the upregulation of various cytokines to clear the infected cells. IL-23 has an essential function in immune networks, can induce IL-17 production, and can antagonize inhibition from IL-12 in the presence of T helper (Th) 17 cells, resulting in type II IFN (IFN-γ) regulation. IL-27 has a competitive relationship to IL-35 because they both include the same subunit, the Epstein–Barr virus-induced gene3 (EBi3). This review provides a simple introduction to the IL-12 family and focuses on their functions relevant to their actions to counteract viral infections.

Immunoregulatory Functions of the IL-12 Family of Cytokines in Antiviral Systems.

The balance between inflammatory and anti-inflammatory immune responses is maintained through immunoregulatory cell populations and immunosuppressive cytokines. Interleukin-35 (IL-35), an inhibitor...

Interleukin-35: Structure, Function and Its Impact on Immune-Related Diseases.

CD4+ T cells orchestrate adaptive immune responses through their capacity to recruit and provide help to multiple immune effectors, in addition to exerting direct effector functions. CD4+ T cells are increasingly recognized as playing an essential role in the control of chronic viral infections. In this review, we present recent advances in understanding the nature of CD4+ T cell help provided to antiviral effectors. Drawing from our studies of natural human immunodeficiency virus (HIV) control, we then focus on the role of high-affinity T cell receptor (TCR) clonotypes in mediating antiviral CD4+ T cell responses. Last, we discuss the role of TCR affinity in determining CD4+ T cell differentiation, reviewing the at times divergent studies associating TCR signal strength to the choice of a T helper 1 (Th1) or a T follicular helper (Tfh) cell fate.

https://www.mdpi.com/1422-0067/22/2/523/pdf

Role of CD4+ T Cells in the Control of Viral Infections: Recent Advances and Open Questions.

Interleukin (IL)-35 regulates imbalance between regulatory T cells (Tregs) and T helper (Th) 17 cells, leading to an important modulator in autoimmune disorder, cancer, and infectious diseases. Our previous study revealed an immunosuppressive activity of IL-35 in chronic hepatitis B virus (HBV) infection. Thus, the aim of the current study was to investigate the role of regulatory function of IL-35 to viral specific Tregs/Th17 cells balance in chronic HBV infection. A total of 44 HLA-A2 restricted chronic HBV infected patients, including 21 of chronic hepatitis B (CHB) and 23 of asymptomatic HBV carriers (ASC) were enrolled. Purified CD4+ T cells or CD4+CD25+CD127dim/− Tregs were stimulated with recombinant IL-35. HBV core antigen specific Tregs and Th17 cells were determined by flow cytometry. FoxP3 and RORγt mRNA was measured by real-time PCR. Cytokines production (IL-10 and IL-17) was investigated by ELISA. Peripheral viral specific Tregs was comparable between CHB and ASC. However, increased percentage of viral specific Th17 cells was found in CHB, leading to the reduction of Tregs/Th17 ratio in CHB patients. IL-35 stimulation elevated viral specific Tregs, but not Th17 cells frequency, in both CHB and ASC, resulting in the elevation of Tregs/Th17 ratio in both groups. This process was accompanied by increased expression of FoxP3 mRNA and IL-10 production, and decreased IL-17 secretion and STAT3 phosphorylation in purified CD4+ T cells. Moreover, IL-35 stimulation inhibited viral specific Th17-like phenotype differentiation from Tregs in CHB patients. Effective anti-HBV therapy did not affect viral specific Tregs/Th17 cells frequency or IL-35 expression in CHB patients, however, reduced responsiveness of CD4+ T cells or Tregs to IL-35 stimulation in vitro. Our findings indicated that IL-35 regulation to viral specific Tregs/Th17 balance may contribute to viral persistence in chronic HBV infection.

/pdf/interleukin-35-modulates-the-balance-between-viral-specific-202518uphk.pdf

Interleukin-35 modulates the balance between viral specific CD4 + CD25 + CD127 dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection

The mechanisms of hepatitis B virus (HBV) persistent infection are not completely understood. Interleukin (IL)-35, which is a newly identified cytokine belongs to IL-12 family, has been demonstrated to induce immunotolerance. Thus, the aim of current study was to investigate the role of IL-35 during chronic HBV infection. A total of 61 patients with chronic HBV infection [37 chronic hepatitis B (CHB) and 24 asymptomatic HBV carriers (ASC)] and 20 healthy individuals were enrolled. IL-35 concentration as well as the modulatory function of IL-35 on CD4+CD25+CD127dim/- regulatory T cells (Tregs) and on HBV antigen-specific CD8+ T cells was investigated. IL-35 expression was significantly increased in both CHB and ASC, and was positively correlated with the levels of HBV DNA. Inhibition of viral replication induced the reduction in serum levels of IL-35. IL-35 stimulation led to inhibition of proinflammatory cytokine productions and elevation of apoptosis in peripheral blood mononuclear cells (PBMCs), but not in HepG2.2.15 cells. Moreover, IL-35 stimulation not only robustly inhibited cellular proliferation, but also up-regulated the production of IL-10 and IL-35 in a HBV antigen-specific and non-specific manner in Tregs/CD4+CD25- T cells coculture system, which indicated enhancement of suppressive function of Tregs. Furthermore, IL-35 also reduced both cytolytic activity (direct lysis of HepG2.2.15 cells) and noncytolytic function (IFN-γ and TNF-α production) of HBV antigen-specific CD8+ T cells. The current data suggested that IL-35 contributed to maintain viral persistence by suppressing antiviral immune responses and reducing inflammatory responses in chronic HBV infection.

/pdf/interleukin-35-suppresses-antiviral-immune-response-in-4ttuiilws1.pdf

Interleukin-35 Suppresses Antiviral Immune Response in Chronic Hepatitis B Virus Infection.

Interleukin (IL)-35 is a newly indentified cytokine and induces immunotolerance via suppression of CD8+ T cell activity in chronic viral hepatitis. To investigate the modulatory function of IL-35 to CD8+ T cells in viral hepatitis-induced acute-on-chronic liver failure (ACLF). Fifty-five ACLF patients and 21 healthy controls were enrolled. Serum IL-35 concentration was measured by ELISA. Absolute accounts for T cells, immune checkpoint molecules, and cytotoxic molecules in CD8+ T cells were measured by flow cytometry and real-time PCR, respectively. Direct and indirect contact co-culture systems between CD8+ T cells and HepG2 cells were set up. The regulatory function of IL-35 to CD8+ T cells was assessed by measuring lactate dehydrogenase expression and cytokine production. Serum IL-35 concentration was elevated in ACLF patients and positively correlated with total bilirubin, but negatively correlated with prothrombin time activity. Peripheral CD8+ T cells showed exhausted phenotype in ACLF patients, which manifested as up-regulation of programmed death-1 (PD-1), cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), and lymphocyte activation gene-3 (LAG-3) but down-regulation of perforin, granzyme B, and FasL. Recombinant IL-35 stimulation dampened cytotoxicity and interferon-γ production in both direct and indirect contact co-culture systems. This process was accompanied by elevation of PD-1, CTLA-4, and LAG3, as well as reduction of perforin, granzyme B, and FasL in CD8+ T cells. Elevated IL-35 suppressed both cytolytic and non-cytolytic activity of CD8+ T cells in ACLF patients.

Interleukin-35 Suppresses CD8 + T Cell Activity in Patients with Viral Hepatitis-Induced Acute-on-Chronic Liver Failure

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Interleukin-35 Suppresses Antiviral Immune Response in Chronic Hepatitis B Virus Infection.

Interleukin-35 modulates the balance between viral specific CD4 + CD25 + CD127 dim/- regulatory T cells and T helper 17 cells in chronic hepatitis B virus infection

Interleukin-35 Suppresses CD8 + T Cell Activity in Patients with Viral Hepatitis-Induced Acute-on-Chronic Liver Failure