CTLA-4 interferes with the HBV-specific T cell immune response (Review)

Hepatitis B virus (HBV) infection is a major cause of hepatic inflammation. Successful HBV clearance in patients is associated with sustained viral control by effector T cells. Compared with acute hepatitis B, chronic HBV infection is associated with the depletion of T cells, resulting in weak or absent virus-specific T cells reactivity, which is described as 'exhaustion'. This exhaustion is characterized by impaired cytokine production and sustained expression of multiple coinhibitory molecules. Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) is one of many coinhibitory molecules that can attenuate T cell activation by inhibiting costimulation and transmitting inhibitory signals to T cells. Persistent HBV infection results in the upregulation of CTLA-4 on hepatic CD8(+) T cells. This prompts CD8(+) T cell apoptosis, and the activation of cytotoxic T lymphocytes is blocked. Similar to CD8(+) T cells, CD4(+) T helper (Th) cell proliferation is hindered following CTLA-4 upregulation. In addition, the differentiation of CD4(+) Th is polarized toward the Th2/peripherally-inducible T regulatory cell types, increasing the levels of anti-inflammatory cytokines. Conversely, the activation of proinflammatory cells (Th1 and follicular helper T) is blocked, and the levels of proinflammatory cytokines decline. This review summarizes the current literature relevant to T cell exhaustion in patients with HBV-related chronic hepatitis, and discusses the roles of CTLA-4 in T cell exhaustion.