CD8
؉ T cells represent a sizable component of the liver inflammatory infiltrate in chronic hepatitis C and are thought to contribute to immune-mediated tissue injury. Because chronic stimulation may promote the expression by CD8 ؉ T cells of distinct human leukocyte antigen class I-specific natural killer cell receptors (NKRs) susceptible to both inhibiting effector functions and promoting cell survival, we examined the distribution and characteristics of CD8 ؉ T cells with such receptors in chronic hepatitis C patients. NKR CD8 ؉ T cells were detectable in liver and peripheral blood from hepatitis C virus (HCV)infected patients but were not major subsets. However, the frequency of NKG2A ؉ CD8 ؉ in the liver and in a lesser extent in the peripheral blood was positively correlated to histological activity in HCV-infected patients. No such correlation was found with KIR ؉ T cells in liver in HCV-infected patients and with the both NKR CD8 ؉ T cells in hepatitis B virus (HBV) infected patients. Circulating CD8 ؉ T cells expressing KIRs exhibited phenotypic features of memory T cells with exacerbated expression of the senescence marker CD57 in patients. NKG2A ؉ CD8 ؉ T cells were committed T cells that appeared less differentiated than KIR ؉ CD8 ؉ T cells. In HCV-infected patients, their content in perforin was low and similar to that observed in NKG2A ؊ CD8 ؉ T cells; this scenario was not observed in healthy subjects and HBV-infected patients. Both NKG2A and KIRs could inhibit the response of HCVspecific CD8 ؉ T cells ex vivo. Conclusion: These results support the concept that an accumulation in the liver parenchyma of NKR ؉ CD8 ؉ T cells that have functional alterations could be responsible for liver lesions. They provide novel insights into the complexity of liver-infiltrating CD8 ؉ T cells in chronic hepatitis C and reveal that distinct subsets of antigen-experienced CD8 ؉ T cells are differentially sensitive to the pervasive influence of HCV (HEPATOLOGY 2007;46:1375-1386.