Natural killer (NK) cells are a third subtype of lymphocytes besides B and T cells. NK cells provide an important immune function in the defense against viruses and other intracellular pathogens. Unlike B and T cells, NK cells do not exhibit specificity for antigen and they acquired their name because of their propensity to kill cells without prior stimulation by antigen. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize major histocompatibility class I molecules. Surprisingly little is known about receptors that activate the cytotoxic response of NK cells. A major goal of this project is to define the molecular basis of NK cell activation and to characterize the receptors involved. In addition, an in vivo model in mice has been developed to determine how activation and inhibition of NK cells and mast cells are controlled during exposure to various pathogens.The gp49B receptor has an inhibitory activity in both NK cells and mast cells. Mice deficient in the gp49B gene have been generated. Such gp49-deficient mice have been crossed for several generations with a congenic strain of mice in order to obtain a fairly pure genetic background. NK cells developed normally in gp49B-deficient mice and displayed normal cytotoxic activity in vitro. Likewise, mast cells developed normally in gp49B-deficient mice and displayed normal degranulation activity in vitro. The healthy status of gp49B-null mice makes them very suitable for testing the role of gp49B in controlling immune responses during infections, in particular those known to elicit NK or mast cell responses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000842-02
Application #
6431708
Study Section
(LIG)
Project Start
Project End
Budget Start
Budget End
Support Year
2
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Bryceson, Yenan T; Long, Eric O (2008) Line of attack: NK cell specificity and integration of signals. Curr Opin Immunol 20:344-52
Long, Eric O (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70-84
Bryceson, Yenan T; Rudd, Eva; Zheng, Chengyun et al. (2007) Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood 110:1906-15
Long, Eric O (2007) Ready for prime time: NK cell priming by dendritic cells. Immunity 26:385-7
Norris, Hillary H; Peterson, Mary E; Stebbins, Chris C et al. (2007) Inhibitory receptor gp49B regulates eosinophil infiltration during allergic inflammation. J Leukoc Biol 82:1531-41
Rajagopalan, Sumati; Bryceson, Yenan T; Kuppusamy, Shanmuga P et al. (2006) Activation of NK cells by an endocytosed receptor for soluble HLA-G. PLoS Biol 4:e9
Rajagopalan, Sumati; Long, Eric O (2005) Understanding how combinations of HLA and KIR genes influence disease. J Exp Med 201:1025-9
Rajagopalan, Sumati; Long, Eric O (2005) Viral evasion of NK-cell activation. Trends Immunol 26:403-5
Bryceson, Y T; Foster, J A; Kuppusamy, S P et al. (2005) Expression of a killer cell receptor-like gene in plastic regions of the central nervous system. J Neuroimmunol 161:177-82
Riteau, Beatrice; Barber, Domingo F; Long, Eric O (2003) Vav1 phosphorylation is induced by beta2 integrin engagement on natural killer cells upstream of actin cytoskeleton and lipid raft reorganization. J Exp Med 198:469-74

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