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Tolerance of NK cells encountering their viral ligand during development

Department of Microbiology and Immunology, Cancer Research Institute, University of California San Francisco, San Francisco, CA 94143, USA.
Journal of Experimental Medicine (Impact Factor: 13.91). 08/2008; 205(8):1819-28. DOI: 10.1084/jem.20072448
Source: PubMed

ABSTRACT During development, T and B cells encountering their cognate ligands via antigen-specific receptors are deleted or rendered anergic. Like T and B cells, natural killer (NK) cells express certain receptors, such as Ly49H, associated with immunoreceptor tyrosine-based activation motif-bearing adaptor proteins that transmit activating signals through Syk family kinases. Ly49H binds with high affinity to a mouse cytomegalovirus (MCMV)-encoded glycoprotein, m157, but does not recognize self-antigens. For comparison with the behavior of immature T and B cells exposed to foreign antigens, we addressed the fate of Ly49H(+) NK cells that encountered their viral ligand during development by retroviral transduction of bone marrow stem cells with m157. In chimeric mice expressing m157, we observed a reduction in Ly49H(+) NK cells in multiple tissues and less Ly49H on the cell surface. NK cells exposed to m157 during development appeared less mature, produced less interferon gamma when stimulated through Ly49H, and were unable to kill m157-bearing target cells. After MCMV infection, these NK cells were severely impaired in their ability to proliferate. Thus, if immature NK cells encounter ligands for their activating receptors, regulatory mechanisms exist to keep these cells in an unresponsive state.

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    • "In the indicated experiments, 200 µg of a depleting antibody against NK1.1 (clone PK136) was injected intravenously at the time of adoptive transfer. 5 × 10 4 PFU of a salivary gland stock of MCMV (Smith strain) was injected intraperitoneally, as described previously (Sun and Lanier, 2008b). "
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    • "The education of NK cells is also influenced by signals received through activating receptors. In a process analogous to negative selection of developing T cells, ligation of activating receptors on developing NK cells by ubiquitiously expressed cognate viral or self-ligands leads to both a repression of cellular function through that particular receptor and a partial deletion of the subset repertoire (Ogasawara et al., 2005; Oppenheim et al., 2005; Sun and Lanier, 2008b; Tripathy et al., 2008). Altogether , these mechanisms are thought to exist to ensure that mature NK cells do not attack healthy self-tissues. "
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