Virus-specific CD8+ T cells with type 1 or type 2 cytokine profile are related to different disease activity in chronic hepatitis C virus infection

The present study demonstrates that the quality of the virus-specific CD8() T cell responses, as detected by both enzyme-linked immunospot assay and specific MHC-peptide tetramers, changed in relation to the different diseas e activity in chronically hepatitis C virus-infected patients. Indeed, both the serum alanine transaminase and the hepatic flogosis levels were relate d directly to the frequencies of peripheral memory effector CD8(+) T cells producing IFN-gamma (Tc1), but inversely to the frequencies of those produc ing both IL-4 and IL-10 (Tc2). Longitudinal studies highlighted that Tc1 or Tc2 responses fluctuate in relation to the different phases of the disease in the same individual. Furthermore, the Tc1 or Tc2 phenotype correlates w ith tetramer-positive cells expressing either CXCR3 or CCR3, promoting diff erential tissue localization of these cells and the maintenance of T cell h omeostasis. Finally, studies at the level of liver-infiltrating lymphocytes indicated that they produced both IFN-gamma and IL-4 with an evident bias towards the Tc1-like phenotype. Our studies suggest that the progressive fl uctuation of Tc1 and Tc2 responses may play a fundamental role in maintaini ng a long-lasting low-level liver inflammation, and may constitute the basi s for new therapeutic strategies of immune regulation.