MHC class I expression on tumor targets inhibits natural killer cell-mediated cytotoxicity without interfering with target recognition.
NK cell-mediated killing is inversely proportional to the amount of MHC class I expression on certain tumor targets. Two hypotheses have been proposed to explain why class I-bearing targets are more resistant to NK cell-mediated lysis: 1) the presence of class I prevents NK cell recognition of a triggering molecule on the target cell surface, or 2) class I recognition transmits a separate inhibitory signal to the NK cell. To differentiate between these potential mechanisms, we have used cloned human CD16+/CD3- NK cells, the class I-deficient cell line C1R, and C1R cells expressing high levels of transfected HLA class I gene products. If class I expression blocks NK cell recognition of the targets, then proximal cell signaling events such as phospholipase C-mediated hydrolysis of membrane phosphoinositides should be decreased in the NK cells interacting with the class I transfectants. However, we found that increases in the level of target cell class I expressions did not decrease phosphoinositide turnover or calcium signaling in NK cells. We also examined the effect of treating HLA-transfected C1R cells with mAb specific for the transfected MHC class I gene product. If class I expression has a negative regulatory influence on NK cell activation, then treating the targets with anti-HLA mAb should block the transmission of this negative signal. Consistent with this notion, addition of anti-HLA mAb (either whole Ig or F(ab')2 fragments) led to increased lysis of the class I-transfected targets. In contrast, addition of isotype-matched mAb specific for other cell surface markers did not alter sensitivity to lysis. All of these results suggest that MHC class I expression on target cells can initiate inhibitory signals in NK cells without blocking access to target structures.
Kaufman
D S
DS
Department of Immunology, Mayo Clinic and Foundation, Rochester, MN 55905.
Schoon
R A
RA
Leibson
P J
PJ
D002118:Calcium / Q000378:metabolism; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation; D015290:Second Messenger Systems; D015398:Signal Transduction
D015395:Histocompatibility Antigens Class I; D007295:Inositol Phosphates; D002118:Calcium