Natural killer cells are part of the innate immune system, the primary defense against virus infections and tumors. They may also have a role in activating autoimmune diseases. They lyse their target through forming an activating immunological synapse or they are inhibited by forming an inhibitory synapse with these cells. The goal of this project is to understand how the immunological synapses are formed and how they function. This knowledge may help us to enhance (in the case of virus infection or tumors) or diminish (in the case of autoimmune diseases) their cytolytic activity in circumstances in which this may be desired.
The Specific Aim of this proposal is to examine the formation and function of immunological synapses in human Natural Killer (NK) cells by: 1. Identifying the protein components of the actin ring in the peripheral supermolecular activation cluster of the activating NK synapse and the mechanism by which this multiprotein complex is formed, particularly the role of Wiscott-Aldrich Syndrome interacting protein (WIP) and its phosphorylation sites. 2. Studying the signaling pathways that lead to formation of the activating immunological synapse, particularly the phosphorylation of synaptic components and their functions. 3. Defining the role of Myosin IIA and IIB in granule exocytosis, the last step that leads to cytolysis of target cells. ? ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI050207-07
Application #
7370997
Study Section
Innate Immunity and Inflammation Study Section (III)
Program Officer
Miller, Lara R
Project Start
2001-09-30
Project End
2012-02-29
Budget Start
2008-03-01
Budget End
2009-02-28
Support Year
7
Fiscal Year
2008
Total Cost
$409,568
Indirect Cost
Name
Harvard University
Department
Microbiology/Immun/Virology
Type
Schools of Arts and Sciences
DUNS #
082359691
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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