NK Cell Receptors and Their Ligands

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The central focus of our lab is to define the mechanisms responsible for NK cell recognition, and to determine the role of NK cell receptors and their ligands in immunity against virus-infected cells and tumors. In this competitive renewal application, we propose to continue our efforts towards this goal by addressing three promising new areas in human and mouse NK cell biology. Specific aims are: 1) To determine how mouse NK cells use the activating Ly49P receptor to recognize cytomegalovirus (CMV)-infected cells and provide protective anti-viral immunity, 2) To define the specificities of activating human NK cell receptors for ligands presented by virus-infected cells and by dendritic cells, and 3) To evaluate the function of the human NKR-P1A receptor and its ligand. For aim 1, we have preliminary data showing that the activating Ly49P receptor express by NK cells in MCMV-resistant MA/My mice recognizes MCMV-infected cells, but only if the MCMV-infected cells express H-2k suggeting for the first time that NK cell recognition of a pathogen may be MHC-restricted. We outline strategies to define this mechanism of recognition in vitro and vivo. For aim 2, we have established a powerful new function-based expression cloning strategy, and have validated its use in identifying ligands on human EBV-transformed B cells that activated human NK cells. We will now use this strategy to elucidate how human NK cells recognize human CMV-infected cells and how human NK cell interact with dendritic cells. In the final aim, we have recently identified a ligand for the human NKR-P1A (CD161) receptor, and will conduct studies to define the function and signaling resulting from this receptor-ligand interaction. Collectively, this project will further our understanding of how mouse and human NK cells contribute to immunity againts virus-infected cells and tumors.