Natural killer (NK) cells are large granular lymphocytes that spontaneously lyse certain tumor cells and cell lines. We have previously shown that NK cells respond specifically to target cells by stimulating the polyphosphoinositide (PPI) signaling pathway, leading to the generation of inositol phosphates and a rise in intracellular calcium, and we showed that these signals are associated with cytotoxicity. By studying an NK-like rat leukemia cell line, RNK- 16, we have identified two previously unknown surface molecules that can stimulate the PPI pathway. Our proposed studies will examine in detail the function and regulation of one of these, gp42. gp42 is expressed on RNK-16 cells by anchoring to glycosylphosphatidylinositol (GPI): it is the only known GPI-anchored molecule on lymphocytes that can signal in the absence of the T cell receptor. The first goal of our proposed studies is to define the structural requirements for signaling by gp42. A second aspect of our studies involves the restricted expression of gp42 on rat leukocytes. gp42 is not expressed by resting NK cells, but it is uniquely induced on NK cells in response to interleukin-2 (IL-2). It is the only activation antigen that is specific for NK cells. The second goal of our proposed work is to define the genetic regulatory elements that restrict expression of gp42 to activated NK cells. The third goal of our proposal is to clone the cDNA for human gp42 and to use this in developing monoclonal antibodies for the study of human gp42.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Experimental Immunology Study Section (EI)
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
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Daniels, B F; Nakamura, M C; Rosen, S D et al. (1994) Ly-49A, a receptor for H-2Dd, has a functional carbohydrate recognition domain. Immunity 1:785-92
Yokoyama, W M; Seaman, W E (1993) The Ly-49 and NKR-P1 gene families encoding lectin-like receptors on natural killer cells: the NK gene complex. Annu Rev Immunol 11:613-35
Bell, G M; Seaman, W E; Niemi, E C et al. (1992) The OX-44 molecule couples to signaling pathways and is associated with CD2 on rat T lymphocytes and a natural killer cell line. J Exp Med 175:527-36
Ryan, J C; Turck, J; Niemi, E C et al. (1992) Molecular cloning of the NK1.1 antigen, a member of the NKR-P1 family of natural killer cell activation molecules. J Immunol 149:1631-5
Seaman, W E; Niemi, E C; Stark, M R et al. (1991) Molecular cloning of gp42, a cell-surface molecule that is selectively induced on rat natural killer cells by interleukin 2: glycolipid membrane anchoring and capacity for transmembrane signaling. J Exp Med 173:251-60
Yokoyama, W M; Ryan, J C; Hunter, J J et al. (1991) cDNA cloning of mouse NKR-P1 and genetic linkage with LY-49. Identification of a natural killer cell gene complex on mouse chromosome 6. J Immunol 147:3229-36
Ryan, J C; Niemi, E C; Goldfien, R D et al. (1991) NKR-P1, an activating molecule on rat natural killer cells, stimulates phosphoinositide turnover and a rise in intracellular calcium. J Immunol 147:3244-50
Imboden, J B; Bell, G; Seaman, W E (1991) Characterization of signal-transducing molecules on natural killer cells. Biochem Soc Trans 19:265-8
Goldfien, R D; Seaman, W E; Hempel, W M et al. (1991) Divergent regulation of phospholipase C-alpha and phospholipase C-gamma transcripts during activation of a human T cell line. J Immunol 146:3703-8
Imboden, J B; Eriksson, E C; McCutcheon, M et al. (1989) Identification and characterization of a cell-surface molecule that is selectively induced on rat lymphokine-activated killer cells. J Immunol 143:3100-3