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-2ksuggeting 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI068129-08
Application #
7340777
Study Section
Special Emphasis Panel (ZRG1-III (01))
Program Officer
Miller, Lara R
Project Start
2001-01-09
Project End
2011-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
8
Fiscal Year
2008
Total Cost
$355,524
Indirect Cost
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Méndez-Lagares, Gema; Lu, Ding; Chen, Connie et al. (2018) Memory T Cell Proliferation before Hepatitis C Virus Therapy Predicts Antiviral Immune Responses and Treatment Success. J Immunol 200:1124-1132
Nabekura, Tsukasa; Chen, Zhiying; Schroeder, Casey et al. (2018) Crk Adaptor Proteins Regulate NK Cell Expansion and Differentiation during Mouse Cytomegalovirus Infection. J Immunol 200:3420-3428
Sun, Joseph C; Lanier, Lewis L (2018) Is There Natural Killer Cell Memory and Can It Be Harnessed by Vaccination? NK Cell Memory and Immunization Strategies against Infectious Diseases and Cancer. Cold Spring Harb Perspect Biol 10:
Jensen, Helle; Potempa, Marc; Gotthardt, Dagmar et al. (2017) Cutting Edge: IL-2-Induced Expression of the Amino Acid Transporters SLC1A5 and CD98 Is a Prerequisite for NKG2D-Mediated Activation of Human NK Cells. J Immunol 199:1967-1972
Nabekura, Tsukasa; Gotthardt, Dagmar; Niizuma, Kouta et al. (2017) Cutting Edge: NKG2D Signaling Enhances NK Cell Responses but Alone Is Insufficient To Drive Expansion during Mouse Cytomegalovirus Infection. J Immunol 199:1567-1571
Jensen, Helle; Chen, Shih-Yu; Folkersen, Lasse et al. (2017) EBI3 regulates the NK cell response to mouse cytomegalovirus infection. Proc Natl Acad Sci U S A 114:1625-1630
Mukherjee, Sayak; Stewart, David; Stewart, William et al. (2017) Connecting the dots across time: reconstruction of single-cell signalling trajectories using time-stamped data. R Soc Open Sci 4:170811
Mukherjee, Sayak; Jensen, Helle; Stewart, William et al. (2017) In silico modeling identifies CD45 as a regulator of IL-2 synergy in the NKG2D-mediated activation of immature human NK cells. Sci Signal 10:
Lam, Viola C; Lanier, Lewis L (2017) NK cells in host responses to viral infections. Curr Opin Immunol 44:43-51
Crome, Sarah Q; Nguyen, Linh T; Lopez-Verges, Sandra et al. (2017) A distinct innate lymphoid cell population regulates tumor-associated T cells. Nat Med 23:368-375

Showing the most recent 10 out of 105 publications