A group of lymphocytes called natural killer (NK) cells can kill several kinds of cells almost indiscriminately. Although NK cells serve useful functions in immune responses against certain viruses, parasites, and tumor cells, they are also dangerous as they exhibit potent killing activity. Therefore, the mechanisms in place to prevent killing of normal cells by NK cells serve an essential function. It is important to understand how such regulation of NK activity is achieved. The killing of normal healthy cells is prevented by inhibitory receptors on NK cells that recognize surface molecules called major histocompatibility complex class I (MHC class I). A major goal of this project is to define the molecular basis of MHC class I recognition by the inhibitory receptors on NK cells and how recognition of MHC class I by the receptor results in a negative signal transmitted to the NK cell. In addition, the regulation of NK cell activity by inhibitory receptors serves as a model to study other receptor systems that use a similar mode of negative regulation. NK cells express a family of related molecules called killer cell immunoglobulin-like receptors (KIR). KIR exert their inhibitory function by recruiting the tyrosine phosphatase SHP-1 to an amino acid sequence motif, called immunoreceptor tyrosine-based inhibition motif (ITIM), in their cytoplasmic tail. Three members of the KIR family are specific for the human MHC class I molecules HLA-C. Biochemical experiments established that KIR can form two types of dimers, each of which binds HLA-C with greater affinity than the KIR monomer. Significant progress was made in understanding how KIR inhibits NK cell activation. Binding of KIR to HLA-C on target cells prevented the phosphorylation of the activation receptor CD244. Therefore, KIR molecules can act at a step as early as phosphorylation of an activation receptor. One of the earliest steps in target cell recognition by NK cells is the formation of a conjugate that involves adhesion molecules. An assay for conjugate formation was used to show that adhesion to a target cell expressing cognate HLA-C was disrupted by KIR engagement. Conjugate formation was interrupted abruptly by KIR within less than five minutes. Inhibition of adhesion to target cells was mediated by a chimeric KIR molecule carrying the tyrosine phosphatase SHP-1 in place of its cytoplasmic tail, showing that SHP-1 can inhibit signals that lead to cell adhesion. These results suggest that other ITIM-bearing receptors, many of which have no known function, may regulate adhesion in a wide variety of cell types.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Intramural Research (Z01)
Project #
1Z01AI000525-13
Application #
6431581
Study Section
(LIG)
Project Start
Project End
Budget Start
Budget End
Support Year
13
Fiscal Year
2000
Total Cost
Indirect Cost
Name
Niaid Extramural Activities
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Bryceson, Yenan T; Ljunggren, Hans-Gustaf; Long, Eric O (2009) Minimal requirement for induction of natural cytotoxicity and intersection of activation signals by inhibitory receptors. Blood 114:2657-66
Long, Eric O (2008) Negative signaling by inhibitory receptors: the NK cell paradigm. Immunol Rev 224:70-84
Peterson, Mary E; Long, Eric O (2008) Inhibitory receptor signaling via tyrosine phosphorylation of the adaptor Crk. Immunity 29:578-88
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
Bryceson, Yenan T; March, Michael E; Ljunggren, Hans-Gustaf et al. (2006) Synergy among receptors on resting NK cells for the activation of natural cytotoxicity and cytokine secretion. Blood 107:159-66
Bryceson, Yenan T; March, Michael E; Ljunggren, Hans-Gustaf et al. (2006) Activation, coactivation, and costimulation of resting human natural killer cells. Immunol Rev 214:73-91
Bryceson, Yenan T; March, Michael E; Barber, Domingo F et al. (2005) Cytolytic granule polarization and degranulation controlled by different receptors in resting NK cells. J Exp Med 202:1001-12
Eissmann, Philipp; Beauchamp, Lisa; Wooters, Joe et al. (2005) Molecular basis for positive and negative signaling by the natural killer cell receptor 2B4 (CD244). Blood 105:4722-9
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
Barber, Domingo F; Faure, Mathias; Long, Eric O (2004) LFA-1 contributes an early signal for NK cell cytotoxicity. J Immunol 173:3653-9

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