Activation of c-Jun N-terminal kinase in the absence of NFκB function prior to induction of NK cell death triggered by a combination of Anti-Class I and Anti-CD16 antibodies

Abstract

Addition of antibodies to major histocompatibility complex class I (MHC class I) and F c gamma RIII (CD16) antigens resulted in the synergistic augmentation of natural killer (NK) cell death, and the loss of NK cell cytotoxic function. The binding of anti-CD16 and anti-class I antibodies to the same population of NK cells is required for the synergistic augmentation of NK cell death. Moreover, the addition of antibodies to leukocyte function antigen-1 (LFA-1), which significantly inhibited the phorbol 12-myristate 13-acetate (PMA) and ionomycin mediated NK cell death, had no effect on NK cell death mediated by anti-CD16 and anti-class I antibodies. The increase in NK cell death was associated with an increase in tumor necrosis factor-α (TNF-α) secretion, and concomitant inhibition of nuclear factor kappa B (NFκB) activation and the induction of c-jun N-terminal kinase (JNK) activity in NK cells treated with the combination of anti-class I and anti-CD16 antibodies. Furthermore, the inhibition of NFκB activation in anti-CD16 and anti-class I antibody treated NK cells was paralleled with a significant increase in inhibitor of kappa B (IκB) protein expression. Overexpression of IκB super-repressor in YT, a NK cell line, caused significant up-regulation of TNF-α, PMA and ionomycin and Fusobacterium nucleatum mediated NK cell death. Overall, our studies suggest an important regulatory role for NFκB and JNK activities in MHC class I mediated NK cell death.