Hybrid resistance by mouse NK cells in vitro.

Department of Pathology, University of Texas Southwestern Medical School, Dallas, USA.
Methods in Molecular Biology (Impact Factor: 1.29). 02/2000; 121:73-9. DOI: 10.1385/1-59259-044-6:73
Source: PubMed


The study of hybrid resistance was greatly aided by the development of an in vitro assay by Chadwick and Miller (1). The assay allows one to test for the presence of negative or positive signaling in natural killer (NK) cells, and the ability
of monoclonal antibodies (MAbs) or F(ab′)2 reagents to block those signals. There is already good evidence for negative signals between Ly49 NK cell receptors and their
specific class I antigens, e.g., Ly49A and H2-Dd (2). Thus, the inability of H2b Ly49A purified NK cells to kill H2d target cells can be reversed by adding MAb reagents that bind to either Ly49A or H2-Dd. We and others have extended these early findings to the Ly49C and I subsets of NK cells, and have recently detected positive
signaling from D8 (H2b, Dd transgene) to purified H2b Ly49D+ NK cells that can be blocked by antibodies or their F(ab′)2 fragments to Ly49D. The assay can also be used to study signaling properties of fetal and neonatal NK cells lacking Ly49
receptors, which suggest that inhibitory non-Ly49 NK receptors are expressed on such NK cells and that these receptors can
receive negative signals from class I molecules (3,4). The stimulation of bone marrow NK precursor cells with various cytokines, including IL-15, leads to generation of lytic
NK1.1+Ly49- cells whose function is similar to that of fetal NK cells, i.e., they can lyse YAC-1 tumor cells and class I deficient cells,
but cannot lyse normal lymphoblasts and lack Ly49 receptors (5). These two types of in vitro systems allow the analysis of factors necessary for various stages in NK cell differentiation
and positive and negative signaling to NK cells at different stages of maturation.

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    ABSTRACT: NK cells use NKG2D receptor to recognize 'induced-self'. In apparent violation of the 'missing-self' hypothesis, NK cells stimulated through NKG2D can lyse target cells despite normal expression levels of MHC class I molecules. Although, 'overriding' of the inhibitory by the activating signals had been postulated the precise role of inhibitory Ly49 receptors on NKG2D-mediated activation has only started emerging. We propose that NKG2D-mediated activation is a function of 'altering the balance' in the signaling strength between the activating NKG2D and inhibiting Ly49 receptors. Balance in the signaling strength depends on the expression levels of activating ligands on the target cells. Qualitative and quantitative variations of MHC class I molecules expressed on the target cells also plays a major role in determining this 'altered-balance'. Consequently, the nature of Ly49 receptors expressed on specific NK subsets determines the level of NKG2D-mediated NK cell activation. These observations provide a firm basis of 'altered-balance' in NK signaling and describe an active interplay between inhibitory Ly49 and activating NKG2D receptors.
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