CD4+ T Cells in Chronic Hepatitis B and T Cell-Directed Immunotherapy

Abstract

The impaired T cell responses observed in chronic hepatitis B (HBV) patients are considered to contribute to the chronicity of the infection. Research on this impairment has been focused on CD8+ T cells because of their cytotoxic effector function; however, CD4+ T cells are crucial in the proper development of these long-lasting effector CD8+ T cells. In this review, we summarize what is known about CD4+ T cells in chronic HBV infection and discuss the importance and opportunities of including CD4+ T cells in T cell-directed immunotherapeutic strategies to cure chronic HBV.

Immune Checkpoint Molecules Expressed on CD4+ T Cell Subsets in Chronic Asymptomatic Hepatitis B Virus Carriers With Hepatitis B e Antigen-Negative

“…Dysfunctional CD4 + T cells are closely correlated with the upregulation of immune co-inhibitory molecules expressed on CD4 + T cells that usually played an immunosuppressive function, such as TIM-3, PD-1, LAG-3, and CTLA-4 ( Park et al, 2016 ; Salimzadeh et al, 2018 ; Dong et al, 2019 ; Fisicaro et al, 2020 ; Ferrando-Martinez et al, 2021 ). Previous reports showed an increased frequency of PD-1 + CD4 + T cells, TIM-3 + CD4 + T cells, LAG-3 + CD4 + T cells, and CTLA-4 + CD4 + T cells in chronic HBV infection, and the blockade of the co-inhibitory receptors contributed to the restoration of CD4 + T cell proliferation and function and promoted cytotoxic effector of CD8 + T cells that played critical roles in viral clearance and disease pathogenesis of sustained HBV infection ( Peng et al, 2008 ; Dong et al, 2017 , 2019 ; Buschow and Jansen, 2021 ; Xiong et al, 2021 ). However, these studies did not display detailed data on ASCs of patients with chronic HBV.…”

“…Accumulating evidence indicates that high expressions of immune checkpoint molecules (TIM-3, PD-1, CTLA-4, and LAG-3) on CD4 + T cells are related to decreased secretion of cytokines and proliferation capacity of T cells, such as IFN-γ + Th1, IL-4 + Th2, IL-17A + Th17, and IL-21 + Tfh cells, except for PD-1 high Tfh cells that have the capacity of inducing B-cell response and the generation of specific antibodies against antigens or viruses ( Gibney et al, 2016 ; Park et al, 2016 ; Saeidi et al, 2018 ; Buschow and Jansen, 2021 ). However, Treg cells with increased expressions of immune checkpoint molecules displayed a high immunosuppressive function on HBV-specific Th1 and Tfh responses and promoted IL-10 and TGF-ß1 secretion ( Stoop et al, 2005 ; Buschow and Jansen, 2021 ). This study showed that the frequencies of circulating TIM-3 + or PD-1 + Tfh cells and TIM-3, LAG-3, and PD-1 molecules on Th1, Th2, Th17, and Treg cells were significantly expanded in chronic ASCs with HBeAg-negative in comparison with HC, which were partially accordant with previous reports ( Stoop et al, 2005 ; Wang R. et al, 2018 ; Wang X. et al, 2018 ).…”

“…The function of CD8 + T cells can be impaired without the help of CD4 + T cells, and CD8 + T cells contribute to controlling and clearing viruses ( Zuniga et al, 2015 ; Saeidi et al, 2018 ; Sears et al, 2021 ). Unfortunately, the function of CD4 + /CD8 + T cells is dysregulated in CHB infection, which is closely correlated with high expressions of immune checkpoint molecules on them ( Bertoletti and Ferrari, 2012 ; Dong et al, 2019 ; Buschow and Jansen, 2021 ). Therefore, the immune checkpoint molecules on specific CD4 + T cell subsets in chronic HBV infection should be further elucidated in the ASCs with HBeAg-negative, which will contribute to a better understanding of CD8 + T cell dysfunction during CHB infection.…”

CD4+ Memory Stem T Cell in Peripheral Blood: A Promising Immune Index for Early Screening and Auxiliary Diagnosis of Colorectal Cancer

“…In the inclusion and exclusion criteria used in this study, patients with chronic persistent human immunodeficiency virus, hepatitis C virus, and human papilloma virus infections were excluded. Although it is not well-understood whether hepatitis B can cause CD4 + T cell depletion, the immune mechanism of patients with progressive damage due to chronic infection is clear ( 31 , 32 ). However, as many patients have chronic hepatitis B infection, they are not suitable for direct exclusion; therefore, we conducted subgroup analysis.…”

T and NK Cell-Based Immunotherapy in Chronic Viral Hepatitis and Hepatocellular Carcinoma

“…Of course, timing for the succession of different combined interventions needs to be well calibrated: first the viral antigenic burden, including HBeAg, should be reduced by antiviral treatments, then therapeutic vaccination could be considered associated with a Th1 skewing adjuvant, before or after T cell-enhancing drugs. Finally, antiviral therapy suspension can also function as a natural booster, eventually resulting in infected hepatocyte clearance [ 8 ].…”