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Positive Recognition of MHC Class I Molecules by the Ly49D Receptor of Murine NK Cells¹

Thaddeus C. George^*, Llewellyn H. Mason, John R. Ortaldo, Vinay Kumar^* and Michael Bennett^2,*

^* Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX 75235; and Laboratory of Experimental Immunology, Division of Basic Sciences, National Cancer Institute, Frederick Cancer Research and Development Center, Frederick, MD 21702

Members of the murine Ly49 family of receptors have been shown to inhibit and activate NK cell function. Subsets of Ly49-expressing NK cells mediate the rejection of bone marrow cell allografts and the lysis of allogeneic lymphoblasts. In this report we have studied Ly49-mediated positive and negative signaling in an in vitro cytotoxicity assay using sorted NK cell subsets as effectors and a panel of ⁵¹Cr-labeled Con A lymphoblasts as targets in the presence or the absence of Abs to Ly49 and/or class I molecules. Our results demonstrate that the activating receptor Ly49D delivers stimulatory signals for target cell lysis upon interacting with H2-D^d, D^r, and D^sp2, but not H2^b or H2^k class I Ags. On the other hand, the inhibitory receptor Ly49G2 delivers negative signals for target cell lysis upon interacting with D^d, D^r, and H2^k, but not H2^b or D^sp2, class I Ags. Furthermore, Ly49-mediated negative signaling dominates Ly49D-mediated positive signaling. Thus, lysis of class I MHC-bearing targets by NK cells is not merely the consequence of the absence of an Ly49-mediated negative signal, but also requires positive recognition of class I molecules by certain Ly49 receptors. Activation of NK cells by nonself class I molecules was not predicted by the missing self hypothesis.

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