The percentage of NK cells in the liver lymphocytes was markedly higher than that in peripheral blood (Fig. 7A). Hepatic NK cells also expressed higher levels of activation markers HLA-DR, CD38, and CD69 (Fig. 7B) and activation receptors NKp30,

NKp44, NKp46, NKG2A, and NKG2D but lower levels of inhibitory receptors CD158a and CD158b (Fig. 7C) in comparison with peripheral NK compartments. Furthermore, hepatic NK cells produced more CD107a than peripheral NK cells with all four stimulations, as described in Fig. 7D. In comparison with peripheral NK cells, hepatic NK cells produced higher levels of IFN-γ only upon PMA/ionomycin stimulation and produced less IFN-γ upon P815/anti-NCR stimulation. These data indicate that hepatic NK cells displayed higher levels of activation and cytotoxic functions than peripheral NK cells in these IA patients. We subsequently Cytoskeletal Signaling inhibitor analyzed the associations between hepatic NK cell activation status and degranulation capacity and liver injury scores in IA patients. As LDE225 shown in Fig. 8A, the expression levels of HLA-DR and CD38 on freshly isolated

hepatic NK cells and CD107a degranulation in response to anti-ALS or anti-NCR were higher in IA patients with inflammation scores of G2 to G3 versus those with a score of G1. On the contrary, CD69 expression on liver NK cells and PMA/ionomycin

and K562 induction of CD107a degranulation were similar between these groups. The correlation Megestrol Acetate analysis further illustrated that the expression of CD38, NKp30, and NCR-redirected CD107a on hepatic NK cells correlated positively with serum ALT levels (all P < 0.05; Fig. 8B). These data suggest that the presence of activated NK cells is closely associated with liver necroinflammation in IA patients. The current study has characterized hepatic and peripheral NK cells in HBV-infected subjects and has demonstrated that (1) activated NK cells preferentially accumulate in the livers of IA patients, in which they are skewed toward cytolytic activity dependent on increased hepatic IL-12, IL-15, and IL-18 expression and decreased IL-10 expression, and (2) the elevated NK cytolytic activity is associated with liver injury, whereas concomitant inefficient IFN-γ production may favor viral persistence in these IA patients. These findings clearly describe the immune status of NK cells in vivo and further define the potential roles of NK cells in liver injury in CHB patients. Although the hepatic NK cell frequency was reduced in IA patients, the total number of hepatic NK cells from these patients was significantly increased, as demonstrated by immunohistochemistry analyses.