The Relation Between Effector and Inhibitory Markers Expressed on CD8+ T Cells in Hepatitis C Virus Infection

Abstract

About 170 million people are infected with hepatitis Cvirus (HCV), which may cause severe liver disease and liver cancer. HCV-specific cytotoxic T lymphocytes (CTLs) play an important role in HCV control during acute infection. Unfortunately, during chronic infection, the reactivity of these cells is impaired after antigen encounter, preventing their effector functions and allowing the development of persistent liver inflammation. The aim of the present study was to identify the role of CD127, KLRG1 and CD57 expressed on the CD8+ T cells specific to HCV as memory and senescence markers in the clearance of HCV infection in seronegative high risk individuals in comparison to non-cleared HCV infection in chronic patients. The study was conducted on 106 individuals who were classified into 3 groups; chronic HCV (47 patients), positive proliferation index high risk group (+PI HRG) (21 patients) and negative proliferation index high risk group (-PI HRG) (38 patients. Primarily, KLRG1, CD127 and CD57 expression was studied on peripheral blood T cytotoxic cells. Only total T cell population (CD3+) was a significantly lower in chronic HCV patients (32.2±20.5) versus both the -PI and the +PI HRG groups. We studied the surface expression of CD127 on cytotoxic T cells after stimulation with different HCV peptides (core, NS3-4 and NS5) using the CFSE proliferation assay. CD3+CD8+CD127+ cell population was significantly higher in proliferating fraction than in non-proliferating fraction in response to the different HCV peptides in chronically infected and the HRGs. However, the percent expression of CD127 was low in all groups (< 25 %) and this down-regulation of CD127 has been attributed to absence of an ongoing antigen recognition. Upon comparing this population between different studied groups, only a significant difference between +PI HRG and –PI HRG was found as regards CD3+CD8+CD127+ cell response to NS5, which was higher among the +PI HRG. Also we studied the percent of CD8+ T cells expressing KLRG-1 specific to HCV peptides using pentamer assay in 5 chronic HCV patients and in 3+ PI HRG. A trend of an increase in percent of the CD 8+ KLRG1+ cells in +PI HRG in response to all pentamer peptides was observed which is indicative of repetitive TCR stimulation but without continuous exposure which was confirmed by the observed decrease in percent of CD8+ T cells expressing CD127 in response to all pentamer peptides. On the other hand, chronic patients showed decreased percentage of CD8+ T cells expressing KLRG1 and CD127 in response to all pentamer peptides except for pentamer peptides core1 (P1) and NS5 (P6). As regard CD57, we observed a higher median percentage in CD8+CD57+ cells specific to different HCV peptides in +PI HRG group and low median percentage in CD8+CD57+ cells specific to different HCV peptides in the chronic HCV patients (except for pentamer peptide core 1) which is another indicative of absence of Ag stimulation despite viral persistance. Based on our findings, it seems that in HRG, the continuous low level exposure to the virus creates waves of effector cells that are capable of clearing the virus while in chronic infection there are long-lived memory cells that are ineffective in clearing the virus as in chronic patients there is no antigen stimulation which was evident by low KLRG1, low CD127 and absence of CD57 on CD8+ T cells. The more focused search in this cell population receptors might answer questions concerning the pathogenesis of HCV infection which may be exploited in the design of more therapeutic approaches for HCV infected patients.