A Distinct Subset of Hyporesponsive Intrahepatic NK Cell is Partially Regulated ny IL-10: Implications for Liver Tolerance

The tolerogenic nature of the liver allows daily exposure to gut-derived foreign antigen without causing inflammation, but may facilitate the establishment of persistent infection in the liver. Natural killer (NK) cells make up a large proportion of the lymphocyte population in the liver, and are critical to both the innate and adaptive immune responses. The presence of immature NK cells in the liver has been reported, but the factor(s) involved in shaping the liver NK cell population remains unclear. We hypothesized that the immature phenotype observed on liver NK cells is due to liver specific regulation, leading to a lower functional capacity by liver NK cells. Compared to splenic NK cells, liver NK cells display a decreased response to IL- 12/IL-18 stimulation. Importantly, the liver contains a significant population of NK cells lacking expression of MHC class I-binding Ly49 receptors, whose expression correlates with greater IFN- production. A large percentage of intrahepatic Ly49 - NK cells express high levels of the inhibitory receptor NKG2A, are poor producers of IFN-, and are the major source of IL-10 among liver NK cells. Splenic NK cells that migrate to the liver following adoptive transfer display phenotypic and functional changes, suggesting that the liver environment can modify NK receptor expression and functional responsiveness. Importantly, IL-10 is present at high levels within the liver, and administration of IL-10 receptor blocking antibody resulted in a decreased percentage of intrahepatic NKG2A + Ly49 - NK cells. These data suggest that the liver environment regulates NK cell receptor expression, and that IL-10 is an important regulatory factor in dampening ii the responsiveness of liver NK cells in part by maintaining a greater percentage of the hyporesponsive NKG2A + Ly49 - NK cells in the liver. Finally, we demonstrate through NK depletion studies that while CD80/CD86 expression on liver DCs is not affected by NK cells, the absolute number of the more mature liver DC population (CD45 + B220 - CD11c + MHCII Hi cells) increases following NK cell depletion. These data have important implications for not only liver tolerance but also for chronic liver disease such as chronic hepatitis C virus infection.

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