The importance of NK cells in controlling viral and bacterial infections, and possibly cancer, is increasingly recognized. Only recently has there been progress in understanding the basis of their specificity. One important component involves recognition of MHC or MHC-like class I molecules. NK cells express inhibitory class I specific receptors that can prevent NK cell activation, cytokine production and target cell lysis. A complete understanding of these receptors and their biological specificity is critical to understanding the function of NK cells in infections and cancer. The investigator proposes to continue efforts to elucidate the function, specificity, repertoire and functional activity of NK class I-specific inhibitory receptors in the mouse, including the Ly49 and CD94/NKG2 receptors, and to examine their role in murine cytomegalovirus (MCMV) infections.
The first aim (1) is to complete the characterization of Ly49 receptor specificity with the use of new mAbs against all the of the Ly49 receptors, and binding studies of Ly49 receptors to class I molecules.
The second aim (2) is to clone murine CD94/NKG2 receptors, produce mAbs against them, examine their specificity for class I molecules, and produce transgenic and knockout mice for further functional analyses.
The third aim (3) is to use anti-Ly49 and anti- CD94/NKG2 mAbs and staining and functional studies to elucidate the nature of the NK cell inhibitory receptor repertoire for self class I molecules.
The fourth aim (4) is to determine the role of the MCMV m144 class I homolog protein in preventing NK cell responses and the role of corresponding NK cell receptors in regulating NK immunity to MCMV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI035021-06
Application #
2759451
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Kehn, Patricia J
Project Start
1993-12-01
Project End
2003-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
6
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of California Berkeley
Department
Biochemistry
Type
Schools of Arts and Sciences
DUNS #
094878337
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Shifrin, Nataliya Tovbis; Kissiov, Djem U; Ardolino, Michele et al. (2016) Differential Role of Hematopoietic and Nonhematopoietic Cell Types in the Regulation of NK Cell Tolerance and Responsiveness. J Immunol 197:4127-4136
Ardolino, Michele; Hsu, Joy; Raulet, David H (2015) Cytokine treatment in cancer immunotherapy. Oncotarget 6:19346-7
Shifrin, Nataliya; Raulet, David H; Ardolino, Michele (2014) NK cell self tolerance, responsiveness and missing self recognition. Semin Immunol 26:138-44
van Bergen, Jeroen; Thompson, Allan; van Pel, Melissa et al. (2013) HLA reduces killer cell Ig-like receptor expression level and frequency in a humanized mouse model. J Immunol 190:2880-5
Xia, Mingcan; Guerra, Nadia; Sukhova, Galina K et al. (2011) Immune activation resulting from NKG2D/ligand interaction promotes atherosclerosis. Circulation 124:2933-43
Vivier, Eric; Raulet, David H; Moretta, Alessandro et al. (2011) Innate or adaptive immunity? The example of natural killer cells. Science 331:44-9
Zijlstra, Maarten; Bix, Mark; Simister, Neil E et al. (2010) Beta 2-microglobulin deficient mice lack CD4-8+ cytolytic T cells. 1990. J Immunol 184:4587-91
Joncker, Nathalie T; Shifrin, Nataliya; Delebecque, Frédéric et al. (2010) Mature natural killer cells reset their responsiveness when exposed to an altered MHC environment. J Exp Med 207:2065-72
Blanchard, Nicolas; Kanaseki, Takayuki; Escobar, Hernando et al. (2010) Endoplasmic reticulum aminopeptidase associated with antigen processing defines the composition and structure of MHC class I peptide repertoire in normal and virus-infected cells. J Immunol 184:3033-42
Joncker, Nathalie T; Fernandez, Nadine C; Treiner, Emmanuel et al. (2009) NK cell responsiveness is tuned commensurate with the number of inhibitory receptors for self-MHC class I: the rheostat model. J Immunol 182:4572-80

Showing the most recent 10 out of 38 publications