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Structure and Function of Natural Killer Cell Receptors

Award Number: R01AI047990
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2000
PERIOD OF PERFORMANCE END DATE: 05/31/2016

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Structure and Function of Natural Killer Cell Receptors - DESCRIPTION (provided by applicant): Natural killer (NK) cells are a fundamental component of innate immunity against tumors and virally infected cells. NK cell function is regulated by a dynamic balance between activating receptors that trigger NK cytolytic activity and inhibitory receptors that detect the lack of normal MHC class I (MHC-I) expression. The past few years have witnessed major advances in our understanding of NK cell function, including the discovery that Ly49 NK receptors not only interact with MHC-I on target cells (in trans), but also with MHC-I on the NK cell itself (in cis), the demonstration that mouse cytomegalovirus (MCMV) evades detection by NK cells by expressing an MHC-like decoy ligand (m157) for Ly49s, and the identification of novel, non-MHC ligands for the orphan NK receptors KLRG1, NKp80, and NKp30. We propose to establish the structural basis for each of these newly discovered NK receptor-ligand interactions using X-ray crystallography, and to correlate this information with analyses of NK cell function. Our objectives are: 1. Basis for Ly49 engagement of MHC-I in cis versus trans. By lowering the threshold for NK cell activation, cis interactions optimize discrimination between normal and diseased cells. Using the structure of a Ly49 receptor with its stalk region, we have constructed a model for cis-trans interactions that we will test at the cellular level through functional and biochemical analyses of structure-based Ly49 mutants. 2. Basis for direct recognition of a viral pathogen by Ly49 receptors. To compare the interaction of NK receptors with viral versus host ligands, we will determine structures of the MCMV protein m157 bound to Ly49I and Ly49H. 3. E-cadherin interactions with KLRG1 and integrin 1E27. The inhibitory receptor KLRG1 directs NK cytolysis against tumors that have lost E-cadherin expression. The structure of KLRG1 bound to E-cadherin suggests an oligomerization model for KLRG1-E-cadherin interactions and implies that E-cadherin can co-engage KLRG1 and 1E27. We will test the oligomerization and co-engagement hypotheses. 4. Basis for cellular cross-talk via the activating receptors NKp80 and AICL. The NKp80-AICL interaction not only promotes NK cell- mediated cytolysis of malignant myeloid cells, but is also crucial for the mutual activation of NK cells and monocytes at inflammation sites. To understand the recognition event underpinning this cross-talk, we will determine the structure of NKp80 bound to AICL. 5. Basis for recognition of BAT3, a tumor- derived nuclear factor, by the natural cytotoxicity receptor NKp30. Following its release from tumor cells, BAT3 binds to NKp30 and triggers NKp30-mediated cytotoxicity. As a nuclear factor, BAT3 defines a completely new class of NK receptor ligand. Moreover, its identification as a danger signal makes the NKp30-BAT3 interaction of special interest for understanding how the immune system recognizes damaged cells. We propose to determine the structure of BAT3 in complex with NKp30.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2017 ( Subtotal = $0 )
2017	2014	UNIVERSITY OF MARYLAND	3112 LEE BLDG 7809 REGENTS DR	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	14	11/3/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2014 ( Subtotal = $334,125 )
2014	2014	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	14	4/30/2014	NON-COMPETING CONTINUATION	$334,125
														Subtotal = $334,125

Issue Date FY: 2013 ( Subtotal = $314,078 )
2013	2013	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	13	5/6/2013	NON-COMPETING CONTINUATION	$314,078
														Subtotal = $314,078

Issue Date FY: 2012 ( Subtotal = $334,125 )
2012	2012	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	12	5/18/2012	NON-COMPETING CONTINUATION	$334,125
														Subtotal = $334,125

Issue Date FY: 2011 ( Subtotal = $334,125 )
2011	2011	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	11	6/7/2011	NON-COMPETING CONTINUATION	$334,125
														Subtotal = $334,125

Issue Date FY: 2010 ( Subtotal = $337,500 )
2010	2010	UNIVERSITY OF MARYLAND	4101 CHESAPEAKE BLDG	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	001	10	6/11/2010	COMPETING CONTINUATION	$337,500
2010	2008	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	9	6/11/2010	NON-COMPETING CONTINUATION	$0
														Subtotal = $337,500

Issue Date FY: 2008 ( Subtotal = $276,259 )
2008	2008	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	9	7/3/2008	NON-COMPETING CONTINUATION	$276,259
														Subtotal = $276,259

Issue Date FY: 2007 ( Subtotal = $281,609 )
2007	2007	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	8	6/20/2007	NON-COMPETING CONTINUATION	$281,609
														Subtotal = $281,609

Issue Date FY: 2006 ( Subtotal = $290,021 )
2006	2006	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	7	7/7/2006	NON-COMPETING CONTINUATION	$290,021
														Subtotal = $290,021

Issue Date FY: 2005 ( Subtotal = $297,000 )
2005	2005	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	6	6/20/2005	NON-COMPETING CONTINUATION	$297,000
														Subtotal = $297,000

Issue Date FY: 2004 ( Subtotal = $297,000 )
2004	2004	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	5	5/7/2004	COMPETING CONTINUATION	$297,000
														Subtotal = $297,000

Issue Date FY: 2003 ( Subtotal = $259,000 )
2003	2003	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	4	6/16/2003	NON-COMPETING CONTINUATION	$259,000
														Subtotal = $259,000

Issue Date FY: 2002 ( Subtotal = $259,000 )
2002	2002	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	3	6/4/2002	NON-COMPETING CONTINUATION	$259,000
														Subtotal = $259,000

Issue Date FY: 2001 ( Subtotal = $259,000 )
2001	2001	MARYLAND BIOTECHNOLOGY INSTITUTE	4321 HARTWICK ROAD	COLLEGE PARK	MD			USA	Allergy and Infectious Diseases Research	000	2	6/19/2001	NON-COMPETING CONTINUATION	$259,000
														Subtotal = $259,000

Issue Date FY: 2000 ( Subtotal = $259,000 )
2000	2000	MARYLAND BIOTECHNOLOGY INSTITUTE	701 E PRATT STREET, SUITE 200	BALTIMORE	MD	21202	BALTIMORE CITY	USA	Allergy and Infectious Diseases Research	000	1	7/20/2000	NEW	$259,000
														Subtotal = $259,000

Grand Total All Awards = $4,131,842

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Structure and Function of Natural Killer Cell Receptors

Award Number: R01AI047990

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2000

PERIOD OF PERFORMANCE END DATE: 05/31/2016

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