Analysis Of The Function Of Epitope-specific Cytotoxic T Lymphocytes In Chronic Viral Hepatitis B Infection

Despite the existence of effective vaccines against hepatitis B virus (HBV) for many years and massive prophylactic vaccination campaigns, HBV infection remains to be an important health problem worldwide. Approximately 360-million world population is persistently infected with HBV, carrying a greatly increased risk of developing chronic liver inflammation leads to cirrhosis and hepatocellular carcinoma. Mechanism of virus chronic infection remains discussed and we highlight the implication of this new understanding for the optimization of vaccine strategies. Since the virus is preferentially hepatotropic and not cytopathic, HBV-specific cytotoxic T-lymphocytes (CTLs) are thought to play key roles in viral control and liver damage. On recognition of viral antigens, CDS* T cells are activated to kill virus-infected cells by excretion of perform and granzymes or by Fas/FasL triggering, or they inhibit viral replication by releasing cytokines, most notably interferon-v. However, new data has led to a reappraisal of the role of CTL in the control of HBV replication. Several reports have shown that when virus infect hepatocytes, their replication was more likely to be controlled by intracellular inactivation mediated by cytokines than by hepatocytes death. Flow cytometric analysis of a tetrameric HLA-peptide complex is a novel technique that allows direct measurement of each CTL population against viral peptides. The development of HLA-peptide tetrameric complexes to directly visualize HBV specific CD8+ T cells has recently provided the opportunity to investigate the relationship between HBV-specific CDS* T cells and liver damage in more details. Two models for human T cell differentiation have been proposed. The first model is based on the expression of CCR7 defined two subsets of memory cells: central memory OCM) and effector memory cells (TEw)- Champagne et al. who compared HIV- and CMV-specific CDS* T cells further developed this model. These reports indicate a lineage * This work is supported by the Major State Basic Research Development Program of China (973 Program), No.2001 CBS 10001, the Major Programs of the National Natural Science Foundation of China, No. 11111111 differentiation pattern in which naive cells (CD45RA*CD62L*CCR7+) upon encounter with an Ag mature into central memory cells (CD45RA^CD62L+CCR7*), effector memory cells (CD45RA^CD62L"CCR7⁾, and finally terminally differentiated effector cells (CD45RA* CD62UCCR7"). The second model is based on the down-regulation of the costimulatory molecules CD27 and CD28 which, along with CD45RA, define three subsets of human CDS T cells: naive cells (CD45RA*CD27*CD28*), memory cells (CD45RA"CD27+CD28+), and effector cells (CD45RA*CD27^CD28"). The expression pattern of CD27, in combination with CD45 and/or CD28 expression, reflects distinct stages of a gradual linear differentiation from a typical memory T cell (CD27*), with high proliferate capacity and low cytolytic activity, to a highly differentiated T cell (CD27"), with strong effector functions, such as direct cytolytic capacity due to high expression of effector molecules like perform and granzymes. A number of recent studies using subset marker analysis have now shown that in HIV-1-infected individuals, HTV-1 -specific CD4*> CDS* T cells exist predominantly in a preterminally differentiated state, if compared with CMV- specific CDS* T cells in the same individuals. This delayed phenotype correlates with decreased perform and EFN-y expression, which may permit virus to evade CD8+ CTL and CD4* T cells reponses. Impaired maturation is not only confined to HIV specific CDS* T cells but could also be involved in failing immunity to Epstein-Barr virus and other viral infections or tumor patients. Based on these results, we propose that failure immune control in human HBV viral infection could be a result of impaired CTLs maturation into fully differentiated effector T cells. At first, the frequencies of epitope-specific CTLs were determined by using teramer. Subsequently, we used in parallel...