The Different Expression Of Tim-3 In T Cells And NK Cells And The Clinical Relevance In Chronic Hepatitis B Virus Infection

Recent studies have shown that Tim-3?T cell immunoglobulin domain and mucin domain-3?is expressed in cytotoxic T cells,dendritic cells,and NK cells,in addition to Th1 cells.By affecting the function of these cells they are involved in the development of various diseases.Since T cells and NK cells play an important role in HBV infection control and clearance in patients with HBV,Tim-3 may influence disease status in the long-term natural history.The course of chronic hepatitis B is a dynamically balanced natural course.According to the age of infection and host immune system changes,the latest ASSLD guideline for the prevention and treatment of chronic hepatitis B divides the natural course of HBV infection into immune tolerance period?IT?,immune activity period?IA?,immune control period?IC?,and gray area?GZ?.The immune status of each period is different,and the functions of various immune cells in the host are also different.The immune tolerance stage?IT?is considered as immune deficiency,and the elevated transaminase in immune activity stage?IA?is considered as a sign of immune arousal.However,few studies have been reported the expression of Tim-3 on T cells and NK cells in HBV infected patients under different immune states and the role of Tim-3 expression on T cells and NK cells in the clinical liver inflammation and fibrosis of chronic hepatitis b?CHB?remains unclear.Therefore,in this study,the expression of Tim-3 on peripheral blood T cells and their subsets?CD4 and CD8?and the expression of Tim-3 on NK cells and subsets(NK^dim and NK^bright)in patients with HBV infection under different immune states were studied and analyzed.At the same time,the correlations between Tim-3 expression on T cells and NK cells and clinical virology,liver function and liver fibrosis were discussed.Objective:To study the distribution of tim-3 expression in T cells and NK cells and the role of Tim-3 expression of T cells and NK cells in clinical liver inflammation and fibrosis in patients with chronic hepatitis B at different stages.Method:320 patients with chronic hepatitis B at different disease stages were selected,including patients in immune-tolerant phase?IT??31 cases?,immune-active phase?IA??184cases?,inactive CHB phase?IC??48 cases?,and Gray Zone?GZ??57 cases?.17 normal subjects were used as control group?HC=17?.Among 320 patients with chronic HBV infection were enrolled and peripheral blood mononuclear cells?PBMCs?were collected.The frequencies distribution of tim-3 on T cells and their subsets?CD4,CD8?and on NK cells and their subsets(NK^dim,NK^bright)were detected by flow cytometry.The natural course of disease was divided into four groups.The patients were tested for virus,liver function and liver fibrosis.SPSS 24.0 and Graph Pad prism 8 were used to analyze the data.Results:The expressions of Tim-3 on total T,CD4+T and CD8+T cells were significantly higher in IA?immune-active?phase than IT?immune-tolerant?,IC?inactive-carrier?,GZ?gray-zone?phases and healthy controls,while Tim-3 on NK,NK^dim and NK^bright cells was higher in the IT and IC phases which had normal aminotransferase levels.Tim-3 expressions on T and subset cells were found positively associated with liver inflammation?ALT,AST and TBIL?,fibrosis?Fibroscan value and APRI score?and virological features?HBV-DNA,HBs Ag titers and pg RNA?.In contrast,Tim-3 expressions on NK and subset cells were negatively associated with above clinical-virological features.Interestingly,Tim-3 expressions of CD8+T cells were positively correlated with inflammatory cytokines TNF-?+production,however,Tim-3 expressions of NK,NK^dim and NK^bright cells showed negative association with cell inflammatory cytokines production.Conclusion:Tim-3 expression on T cells and NK cells showed contrary characteristics with liver inflammation,fibrosis,virus features and immune cytokines,indicating its different immune roles on different cells in CHB.The findings provide more understandings of the immune status in native hBV infection.