The nonclassical major histocompatibility complex molecule Qa-2 protects tumor cells from NK cell- and lymphokine-activated killer cell-mediated cytolysis.
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.
Chiang
Eugene Y
EY
Center for Immunology, Departments of Microbiology and Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
Henson
Maile
M
Stroynowski
Iwona
I
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002478:Cells, Cultured; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic; D006183:H-2 Antigens / Q000378:metabolism; D006239:Haplotypes; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000502:physiology; D016130:Immunophenotyping; D015979:Killer Cells, Lymphokine-Activated / Q000276:immunology*; D007694:Killer Cells, Natural / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000145:classification / Q000276:immunology; D008545:Melanoma / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D014162:Transfection; D014407:Tumor Cells, Cultured; D010738:Type C Phospholipases / Q000494:pharmacology
D000906:Antibodies; D006183:H-2 Antigens; D015395:Histocompatibility Antigens Class I; D000949:Histocompatibility Antigens Class II; C032907:Q surface antigens; D010738:Type C Phospholipases