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Independent Control of Ly49g Alleles: Implications for NK Cell Repertoire Selection and Tumor Cell Killing¹

Andrew P. Makrigiannis^2,*, Etienne Rousselle^* and Stephen K. Anderson

^* Laboratory of Molecular Immunology, Institut de Recherches Cliniques de Montreal, Montreal, Quebec, Canada; and Basic Research Program, Science Applications International Corporation, National Cancer Institute, Frederick, MD 21702

A novel murine NK cell-reactive mAb, AT8, was generated. AT8 recognizes Ly49G from 129/J, BALB/c, and related mouse strains, but does not bind to Ly49G^B6. Costaining with AT8 and a Ly49G^B6-restricted Ab (Cwy-3) provides the first direct evidence that Ly49G protein is expressed from both alleles on a significant proportion of NK cells from four different types of F₁ hybrid mice. The observed level of biallelic Ly49G expression reproducibly followed the product rule in both freshly isolated and cultured NK cells. Surprisingly, the percentage of NK cells expressing both Ly49G alleles could be dramatically increased in vitro and in vivo through IL-2R- and IFN receptor-dependent signaling pathways, respectively. Unexpectedly, Ly49G^B6+ NK cells in an H-2^d, but not H-2^b, background were more likely to lyse D^d+ and Chinese hamster ovary tumor cells than Ly49G^BALB/129+ NK cells. Furthermore, Ly49G^B6+ NK cells also proliferated to a higher degree in response to poly(I:C) than NK cells expressing a non-Ly49G^B6 allele in an H-2^d, but not H-2^b, background. These results suggest that Ly49G^B6 has a lower affinity for H-2D^d than Ly49G^BALB/129, and the genetic background calibrates the responsiveness of NK cells bearing self-specific Ly49. Other H-2D^d receptors on the different Ly49G⁺ NK cell subsets were unequally coexpressed, possibly explaining the disparate responses of Ly49G^B6+ NK cells in different hybrid mice. These data indicate that the stochastic mono- and biallelic expression of divergent Ly49G alleles increases the range of MHC affinities and the functional potential in the total NK cell population of heterozygous mice.

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