Cytotoxic CD4+ T cells in viral hepatitis

Abstract

Summary. CD4⁺ T cells are thought to contribute to antiviral immune responses by secretion of cytokines thereby providing help to CD8⁺ T and B cells. However, perforin‐positive cytotoxic CD4⁺ T cells have been described in human immunodeficiency virus‐positive patients suggesting a role not only of CD8⁺ but also of CD4⁺ T cells for killing virus‐infected cells. We investigated 76 patients with viral hepatitis [15 hepatitis B virus (HBV), 22 HBV/hepatitis D virus and 17 hepatitis C virus (HCV)] for cytotoxic CD4⁺ T cells. The frequency of perforin‐positive CD4⁺ T cells in viral hepatitis was highly variable ranging from + T cells displayed the phenotype of terminally differentiated effector cells (CD28⁻, CD27⁻). The highest frequencies of CD4⁺ cytotoxic T lymphocytes (CTLs) were found in patients with delta hepatitis (P = 0.04 vs HBV and HCV patients), and the presence of CD4⁺ CTLs was associated with elevated aspartate aminotransferase levels (P = 0.01) and decreased platelet counts (P = 0.03). Perforin‐positive CD4⁺ T cells decreased in two individuals during spontaneous clearance of acute hepatitis C. Significant associations were found between the frequency of perforin‐expressing CD4⁺ cells and age (P = 0.04), perforin‐positive CD8⁺ cells (P < 0.001) and perforin‐positive CD4⁻/CD8⁻ lymphoid cells (P = 0.002). Differentiated CD27⁻ effector CD4⁺ CTLs can be detected in patients with viral hepatitis. In particular in patients with more advanced liver disease, the accumulation of perforin‐positive T cells with age could be one correlate for the more severe course of viral hepatitis in elderly individuals.