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.

  • Source
    • "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). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Cells of the immune system undergo homeostatic proliferation during times of lymphopenia induced by certain viral infections or caused by chemotherapy and radiation treatment. Natural killer (NK) cells are no exception and can rapidly expand in number when placed into an environment devoid of these cells. We explored the lifespan and function of mouse NK cells that have undergone homeostatic proliferation in various settings of immunodeficiency. Adoptive transfer of mature NK cells into lymphopenic mice resulted in the generation of a long-lived population of NK cells. These homeostasis-driven NK cells reside in both lymphoid and nonlymphoid organs for >6 mo and, similar to memory T cells, self-renew and slowly turn over at steady state. Furthermore, homeostatically expanded NK cells retained their functionality many months after initial transfer and responded robustly to viral infection. These findings highlight the ability of mature NK cells to self-renew and possibly persist in the host for months or years and might be of clinical importance during NK cell adoptive immunotherapy for the treatment of certain cancers.
    Journal of Experimental Medicine 02/2011; 208(2):357-68. DOI:10.1084/jem.20100479 · 13.91 Impact Factor
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The development and function of natural killer (NK) cells is dictated by signals received through activating and inhibitory receptors expressed on the cell surface. During their maturation in the bone marrow, NK cells undergo an education process that ensures they are tolerant to healthy peripheral tissues. Several recent studies advance our understanding of self-tolerance mechanisms at work in NK cells. These studies demonstrate that the developmental programming in NK cells is not fixed, and that perturbations to the peripheral environment (via transplantation or viral infection, for example) greatly influence the ability of mature NK cells to mount an effector response. This newfound ability of mature NK cells to be "re-educated" may be clinically applicable in the immunotherapeutic use of NK cells against infection and cancer.
    Journal of Experimental Medicine 09/2010; 207(10):2049-52. DOI:10.1084/jem.20101748 · 13.91 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The paper explains an object-oriented virtual integration approach of heterogeneous distributed databases, which is used in CIMBASE+. We introduce the basic concepts and features of the global data model OSAM* and global data language OSDL of CIMBASE+, explain the virtual schema integration approach, and describe the manipulation process of the virtual integrated database
    TENCON '93. Proceedings. Computer, Communication, Control and Power Engineering.1993 IEEE Region 10 Conference on; 11/1993
Show more

Preview (3 Sources)

Available from