The specific aims of this research are to examine some aspects of the receptor, ligands, and functions of human Natural Killer (NK) cells. In particular, we wish: 1. To study the formation of both the inhibitory and the lytic NK immunologic synapse. 2. To identify the ligands on target cells for the multiple lysis activating receptors on human NK cells. 3. To examine human decidual lymphocytes with respect to NK cells and Natural Killer T (NKT) cells, including their frequency, genotype, and functions (especially production of cytokines and their possible role in implantation and pregnancy) and to examine the possible relationship between Killer cell Immunoglobulin-like Receptor (KIR) haplotype variations and recurrent pregnancy loss. 4. To examine KIR with respect to a) identification of the KIR3D that differentially recognizes HLA-B2705 and HLA-B2702 and b) generation of monoclonal antibodies recognizing the unusual KIR2DL4 and KIR2DL5 that could be used in studies of their polymorphism, ligands, and functions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050207-02
Application #
6532880
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Hackett, Charles J
Project Start
2001-09-30
Project End
2006-05-31
Budget Start
2002-08-01
Budget End
2003-05-31
Support Year
2
Fiscal Year
2002
Total Cost
$410,874
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
071723621
City
Cambridge
State
MA
Country
United States
Zip Code
02138
Krzewski, Konrad; Gil-Krzewska, Aleksandra; Watts, James et al. (2011) VAMP4- and VAMP7-expressing vesicles are both required for cytotoxic granule exocytosis in NK cells. Eur J Immunol 41:3323-9
Allan, David S J; Rybalov, Basya; Awong, Geneve et al. (2010) TGF-ýý affects development and differentiation of human natural killer cell subsets. Eur J Immunol 40:2289-95
Li, Changlin; Ge, Baoxue; Nicotra, Matthew et al. (2008) JNK MAP kinase activation is required for MTOC and granule polarization in NKG2D-mediated NK cell cytotoxicity. Proc Natl Acad Sci U S A 105:3017-22
Krzewski, Konrad; Strominger, Jack L (2008) The killer's kiss: the many functions of NK cell immunological synapses. Curr Opin Cell Biol 20:597-605
Andzelm, Milena M; Chen, Xi; Krzewski, Konrad et al. (2007) Myosin IIA is required for cytolytic granule exocytosis in human NK cells. J Exp Med 204:2285-91
Chen, Xi; Trivedi, Prachi P; Ge, Baoxue et al. (2007) Many NK cell receptors activate ERK2 and JNK1 to trigger microtubule organizing center and granule polarization and cytotoxicity. Proc Natl Acad Sci U S A 104:6329-34
Keskin, Derin B; Allan, David S J; Rybalov, Basya et al. (2007) TGFbeta promotes conversion of CD16+ peripheral blood NK cells into CD16- NK cells with similarities to decidual NK cells. Proc Natl Acad Sci U S A 104:3378-83
Deng, Lih-Wen; Chiu, Isaac; Strominger, Jack L (2004) MLL 5 protein forms intranuclear foci, and overexpression inhibits cell cycle progression. Proc Natl Acad Sci U S A 101:757-62
Orange, Jordan S; Harris, K Eliza; Andzelm, Milena M et al. (2003) The mature activating natural killer cell immunologic synapse is formed in distinct stages. Proc Natl Acad Sci U S A 100:14151-6
Orange, Jordan S; Ramesh, Narayanaswamy; Remold-O'Donnell, Eileen et al. (2002) Wiskott-Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses. Proc Natl Acad Sci U S A 99:11351-6

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