A NEW MECHANISM OF NK CELL CYTOTOXICITY ACTIVATION - THE CD40-CD40 LIGAND INTERACTION

NK recognition is regulated by a delicate balance between positive sig nals initiating their effector functions, and inhibitory signals preve nting them from proceeding to cytolysis. Knowledge of the molecules re sponsible for positive signaling in NK cells is currently limited. We demonstrate that IL-2-activated human NK cells can express CD40 ligand (CD-40L) and that recognition of CD40 on target cells can provide an activation pathway for such human NK cells. CD40-transfected P815 cell s were killed by NK cell lines expressing CD40L, clones and PBL-derive d NK cells cultured for 18 h in the presence of IL-2, but not by CD40L -negative fresh NK cells. Cross-linking of CD40L on IL-2-activated NK cells induced redirected cytolysis of CD40-negative but Fc receptor-ex pressing P815 cells. The sensitivity of human TAP-deficient T2 cells c ould be blocked by anti-CD40 antibodies as well as by reconstitution o f TAP/MHC class I expression, indicating that the CD40-dependent pathw ay for NK activation can be downregulated, at least in part, by MHC cl ass I molecules on the target cells. NK cell recognition of CD40 may b e important in immunoregulation as well as in immune responses against B cell malignancies.