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.

Public Health Relevance

This project aims to better understand how a component of the immune system, the natural killer (NK) cell, works to fight infections. Until now, scientists thought that all NK cells circulate throughout the body in the blood stream. Here we plan to study a novel type of NK cell that appears to reside in the liver and are more potent after being exposed to chemicals or viruses. Understanding the role of these liver-resident NK cells will enable scientists to harness NK cells for treatment of infections and also cancers.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-BDP-M (M1))
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Miller, Lara R
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Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
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Victorino, Francisco; Sojka, Dorothy K; Brodsky, Kelley S et al. (2015) Tissue-Resident NK Cells Mediate Ischemic Kidney Injury and Are Not Depleted by Anti-Asialo-GM1 Antibody. J Immunol 195:4973-85
Sojka, Dorothy K; Plougastel-Douglas, Beatrice; Yang, Liping et al. (2014) Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. Elife 3:e01659
Sojka, Dorothy K; Tian, Zhigang; Yokoyama, Wayne M (2014) Tissue-resident natural killer cells and their potential diversity. Semin Immunol 26:127-31
Peng, Hui; Jiang, Xiaojun; Chen, Yonglin et al. (2013) Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest 123:1444-56