Increased levels of arginase in patients with acute hepatitis B suppress antiviral T cells
July 6, 2015
BACKGROUND & AIMS: During viral infection, the activities of virus-specific CD8(+) T cells are carefully regulated to prevent severe damage of the infected organs. We investigated the mechanisms that control the functions of activated T cells. METHODS: We measured the size of the population of activated and proliferating CD8(+) T cells and the functional pattern of CD8(+) T cells specific for the entire hepatitis B virus proteome and for selected heterologous virus (Epstein-Barr virus, human cytomegalovirus, and influenza virus) using blood samples from 18 patients with acute hepatitis B. We analyzed the effects of different modulatory mechanisms, such as inhibitory molecules, suppressive cytokines (interleukin-10), and arginase, on the activities of CD8(+) T cells. RESULTS: In patients with acute hepatitis B, the expansion of activated and proliferating (HLA-DR/CD38(+), Ki-67(+)/Bcl-2(low)) CD8(+) T cells did not quantitatively match their specific functions ex vivo; virus-specific CD8(+) T cells had functional impairments that were temporally restricted to the acute phase of viral hepatitis. These impairments in function were not limited to HBV-specific CD8(+) T cells but were also observed in CD8(+) T cells with specificities for other viruses. We investigated possible causes of antigen-independent CD8(+) T cell inhibition and found that the increased levels of arginase observed in patients with acute hepatitis could suppress the function of activated, but not resting, CD8(+) T cells. CONCLUSIONS: The increased level of arginase in patients with acute hepatitis B suppresses the functions of activated CD8(+) T cells. This mechanism might limit the amount of liver damage caused by activated CD8(+) T cells in patients with acute HBV infection.
Sandalova, E.; Laccabue, D.; Boni, C.; Watanabe, T.; Tan, A.; Zong, H. Z.; Ferrari, C.; Bertoletti, A.