Exhausted phenotype of circulating CD8+ T cell subsets in hepatitis B virus carriers

Abstract

Background Chronic hepatitis B virus (HBV) infection is characterized by the presence of dysfunctional exhausted CD8+ T cells that hamper viral control. We investigated the phenotypic heterogeneity of exhausted CD8+ T cells in HBV carriers. Methods We enrolled 31 HBV carriers and 23 healthy controls (HCs) in our study. Peripheral blood mononuclear cells (PBMCs) were isolated, and flow cytometry was used to determine the phenotypic distribution of CD8+ T cell subsets. Expression of cytokines such as TNF-α and IFN-γ was detected by quantitative reverse transcription–PCR, a fluorescence flow cytometry-based immunomicrobead assay and flow cytometry. Results There were no significant differences in the baseline characteristics between the 31 HBV carriers and the 23 sex- and age-matched HCs. CD8+ T cells exhibited higher levels of inhibitory receptors (TIM3 and PD1) in the HBV carriers than in the HCs (P < 0.05); in particular, Tfc cells (CXCR5+CD25−) expressed higher levels of TIM3 and PD1 than non-Tfc cells in the HBV carriers. In addition, among the subsets of Tc cells, the Tc17 (CXCR5−CD25−CCR6+) subset displayed increased expression of TIM3 and LAG3 in the HBV carriers. Our findings further showed that CD8+ T cells produced lower levels of IFN-γ, TNF-α, and Granzyme B. Paired analysis of the Tfc subset and the Tc subset indicated that higher levels of cytokines (IFN-γ and TNF-α) were produced by the Tfc subset in the HBV carriers. Among the Tc subsets, the Tc17 subset produced lower levels of cytokines. Conclusion The Tfc subset exhibited an enhanced exhausted phenotype but possessed some functional properties during chronic HBV infection, while the Tc subset showed a lower functional level. The identification of these unique subsets may provide a potential immunotherapeutic target in chronic HBV infection.

The Role of CTLA-4 in T Cell Exhaustion in Chronic Hepatitis B Virus Infection

“…All included patients were chronically infected with HBV. The exclusion criteria of the included studies were similar, as most studies excluded patients coinfected with other hepatitis viruses and/or human immunodeficiency virus (HIV) [ 11 , 17 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 29 , 30 , 31 ], with concurrent liver disease [ 16 , 21 , 22 , 23 , 24 , 26 , 29 , 30 ], and/or patients receiving antiviral or immunomodulatory therapy [ 11 , 15 , 16 , 17 , 21 , 23 , 24 , 28 , 30 ]. One study did not provide detailed information on patients’ inclusion or exclusion criteria [ 9 ].…”

“…Jiang et al [ 22 ] investigated the phenotypic heterogeneity of exhausted CD8 + T cells in the peripheral blood of 31 CHB patients and 23 healthy controls. Compared to healthy controls, CD8 + T cells in CHB patients had higher expression levels of the inhibitory receptors lymphocyte-activation gene 3 (LAG3) and T cell immunoglobulin and mucin domain-containing protein 3 (TIM3).…”

Role of CXCR5+CD8+ T cells in human hepatitis B virus infection

“…Further studies showed that these CD8 + T-cells produced lower levels of IFNγ, tumour necrosis factor α, and granulozyme B. 43 tinctly promoted the production of antibodies by B-cells. 44 In addition, several studies have found that the high frequency of CXCR5 + CD8 + T-cells was associated with a lower HBV DNA load and decreased HBsAg concentration and was negatively correlated with ALT level.…”

“…Studies have shown that the levels of inhibitory receptors (such as TIM3 and PD‐1) on the surface of CD8 + T cells in HBV carriers are higher than those in healthy controls. Further studies showed that these CD8 + T‐cells produced lower levels of IFN‐γ, tumour necrosis factor α, and granulozyme B 43 . CXCR5 + CD8 + T‐cells in the peripheral blood of CHB patients and HBV‐related hepatocellular carcinoma (HCC) patients were significantly up‐regulated compared to healthy individuals.…”

Abnormal glucose metabolism in virus associated sepsis

“…CD8+ T cells are essential IFN γ-mediated non-cytopathic mechanisms to clear HBV. However, in chronic HBV infection, CD8+ T cells are very few and appear to be exhausted, resulting in an obstruction of viral control ( Jiang et al., 2022 ). Exhausted CD8+ T cells achieve metabolic recombination for glycolysis by increasing GLUT1 expression, thereby rapidly providing energy and metabolites to support proliferation and effector T-cell metabolic changes to meet antiviral requirements, although glycolysis is less energy efficient than the TCA cycle ( Schurich et al., 2016 ), and hence interference with glycolysis may lead to T lymphocyte dysfunction ( Zhou X. et al., 2021 ).…”