This proposal on liver-resident NK cells represents a collaboration between the laboratories of Professor Zhigang Tian at University of Science and Technology in China and Dr. Wayne Yokoyama at Washington University in St. Louis. As major components of the innate immune system, natural killer (NK) cells provide host defense against pathogens and developing tumors. Classically the innate immune system is described as having no memory and NK cell functional capacities do not require prior sensitization but memory-like features have been recently described for NK cells, particularly from the liver of mice sensitized with haptens or exposed to viruses. However, splenic NK cells did not show memory-like features in these experiments, suggesting that liver and splenic NK cells have phenotypic differences. Herein preliminary data from the Tian laboratory with advice from Dr. Yokoyama strongly suggest that a subpopulation of NK cells selectively resides in the liver. These liver-resident NK cells express phenotypic differences from conventional splenic NK cells, home to the liver, and confer memory-like responses to haptens. These findings lead to the following Specific Aims to examine: 1) Relationship of liver-resident NK cells to pit cells and conventional NK cells; 2) Immunological requirements for liver-resident NK cells; 3) Priming of liver-resident NK cells; and 4) Role of liver-resident NK cells in viral hepatitis. Thus, the proposed studies wil provide novel insight into the role of liver-resident NK cells in host immune defense.