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The Nonclassical Major Histocompatibility Complex Molecule Qa-2 Protects Tumor Cells from NK Cell- and Lymphokine-Activated Killer Cell-Mediated Cytolysis¹

Center for Immunology, Departments of Microbiology and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390

The cytotoxic activity of NK cells is regulated by class I MHC proteins. Although much has been learned about NK recognition of class I autologous targets, the mechanisms of NK self-tolerance are poorly understood. To examine the role of a nonpolymorphic, ubiquitously expressed class Ib Ag, Q9, we expressed it on class I-deficient and NK-sensitive B78H1 melanoma. Presence of this Qa-2 family member on tumor cells partially protected targets from lysis by bulk lymphokine-activated killer (LAK) cells. H-2K^b-expressing B78H1 targets also reduced LAK cell activity, while H-2D^b offered no protection. Importantly, blocking with F(ab')₂ specific for Q9 or removal of this GPI-attached molecule by phospholipase C cleavage restored killing to the level of vector-transfected cells. Experiments with LAK cells derived from H2^b SCID and B6 mice established that NK1.1⁺TCR^- NK and NK1.1⁺TCR⁺ LAK cells were the prevalent cytolytic populations inhibitable by Q9. Treatment of mice with poly(I:C) also resulted in generation of Q9-regulated splenic cytotoxicity. LAK cells from different mouse strains responded to Q9, suggesting that the protective effect of this molecule is not detectably influenced by Ly49 polymorphisms or the presence/absence of Q9 in NK-harboring hosts. We propose that Q9 expressed on melanoma cells serves as a ligand for yet unidentified NK inhibitory receptor(s) expressed on NK1.1⁺ NK/T cells.

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