MHC-Class I antigens regulate both the function and the survival of human peripheral blood NK cells: role of endogenously secreted TNF-alpha.

Abstract

The cytotoxic activity and survival of NK cells are negatively regulated in the presence of antibodies directed against the FCgammaRIII (CD16) surface receptor. The addition of MHC-class I monoclonal antibody (mAb) in combination with CD16 mAb resulted in a significant potentiation of the inhibition of NK cell cytotoxic function and both accelerated kinetics and synergistic induction of cell death in both resting and IL-2-treated human peripheral blood purified NK cells. The potentiating effect of class I MHC monoclonal antibody was specific as monoclonal antibodies directed against other cell surface antigens on NK (e.g., LFA-3, LFA-1, and CD56) had no effect. A correlation was observed between the levels of secreted TNF-alpha and the frequency of NK cell death and the addition of anti-TNF-alpha antibody inhibited NK cell death. The levels of death promoting gene products such as the Fas receptor and the Fas ligand were upregulated in NK cells in the presence of anti-class I and anti-CD16 antibodies. However, anti-Fas antibodies did not block cell death. These findings demonstrate that MHC-class I antigens regulate both TNF-alpha secretion and cell death of anti-CD16 mAb treated NK cells. These results also suggest that MHC-class I antigens regulate the function and survival of activated NK cells.