Impaired natural killer cell self-education and "missing-self" responses in Ly49-deficient mice

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Abstract

Ly49-mediated recognition of MHC-I molecules on host cells is considered vital for natural killer (NK)-cell regulation and education; however, gene-deficient animal models are lacking because of the difficulty in deleting this large multigene family. Here, we describe NK gene complex knockdown (NKCKD) mice that lack expression of Ly49 and related MHC-I receptors on most NK cells. NKCKDNK cells exhibit defective killing of MHCI-deficient, but otherwise normal, target cells, resulting in defective rejection by NKCKD mice of transplants from various types of MHC-I-deficient mice. Self-MHC-I immunosurveillance by NK cells in NKC KDmice can be rescued by self-MHC-I-specific Ly49 transgenes. Although NKCKDmice display defective recognition of MHC-I-deficient tumor cells, resulting in decreased in vivo tumor cell clearance, NKG2D- or antibody-dependent cell-mediated cytotoxicity-induced tumor cell cytotoxicity and cytokine production induced by activation receptors was efficient in Ly49-deficient NK cells, suggesting MHC-I education of NK cells is a single facet regulating their total potential. These results provide direct genetic evidence that Ly49 expression is necessary for NK-cell education to self-MHC-I molecules and that the absence of these receptors leads to loss of MHC-I-dependent "missing-self" immunosurveillance by NK cells. © 2012 by The American Society of Hematology.

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CITATION STYLE

APA

Beĺanger, S., Tu, M. M., Rahim, M. M. A., Mahmoud, A. B., Patel, R., Tai, L. H., … Makrigiannis, A. P. (2012). Impaired natural killer cell self-education and “missing-self” responses in Ly49-deficient mice. Blood, 120(3), 592–602. https://doi.org/10.1182/blood-2012-02-408732

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