Clinical Significance of BTLA and HVEM Expression on Circulating CD4(+) T and CD8(+) T Cells in Chronic Hepatitis B Virus Infection

In this study, B and T lymphocyte attenuator (BTLA) and herpesvirus entry mediator (HVEM) expression on the surface of circulating CD4(+) T and CD8(+) T cells of patients with chronic hepatitis B (CHB) was investigated to explore their relationship with hepatitis B virus (HBV) clinical parameters. Both BTLA and HVEM were significantly upregulated on CD4(+) T and CD8(+) T cells of CHB patients compared with healthy controls (p < 0.01). Intriguingly, in CHB patients, the percentage of BTLA expression was positively correlated with that of HVEM (CD4(+) T cells: r = 0.5461, p < 0.001 and CD8(+) T cells: r = 0.4206, p < 0.01). Moreover, the percentage of BTLA expression was positively correlated with the levels of aspartate aminotransferase (AST) (CD4(+) T cells: r = 0.3136, p < 0.05 and CD8(+) T cells: r = 0.3159, p < 0.05) and alanine aminotransaminase (ALT) (CD4(+) T cells: r = 0.3177, p < 0.05 and CD8(+) T cells: r = 0.3311, p < 0.05). At the same time, the percentage of HVEM expression was also positively correlated with AST levels (CD4(+) T cells: r = 0.3721, p < 0.05 and CD8(+) T cells: r = 0.3325, p < 0.05) and ALT (CD4(+) T cells: r = 0.3689, p < 0.05 and CD8(+) T cells: r = 0.3476, p < 0.05). However, the percentage of BTLA and HVEM expression did not show significant relevance to HBV viral load. Further study demonstrated that BTLA inhibitory signaling could significantly inhibit T cell proliferation, activation, and cytokine production under optimal T cell receptor signaling (p < 0.05). Thereby, our findings indicate that the increased BTLA and HVEM expression on the surface of CD4(+) and CD8(+) T cells might represent a certain clinical significance and be involved in CHB progression during T cell exhaustion.