CD44 IS A CYTOTOXIC TRIGGERING MOLECULE IN HUMAN PERIPHERAL-BLOOD NK CELLS

Previous studies have shown that target cells that bind to CD44 adhesi on molecules on cloned cytotoxic T cells are lysed by the CTL. To dete rmine whether CD44 is also a cytotoxic trigger molecule in human PBL, we tested a bispecific Ab consisting of anti-CD44 Fab cross-linked to a Fab against a target cell Ag, in cytotoxicity assays using PBL as ef fecters. We found that PBL mediated lysis in the presence of the anti- CD44 bispecific Ab provided that the effector cells were stimulated wi th either IL-2 or IL-12. Cell fractionation experiments showed that CD 44-directed cytolysis was mediated exclusively by CD56(+) low buoyant density cells, mainly by NK(CD16(+)) cells, but also to a lesser exten t by CD56(+) T cells. CD44-directed cytolysis appeared in these subset s 24 to 48 h after addition of IL-2 and paralleled the acquisition of Ab-independent (LAK) activity; in contrast, these cells mediated Ab-de pendent cellular cytotoxicity and CD3 redirected lysis before stimulat ion with IL-2. Unstimulated CD56(+) cells uniformly expressed high lev els of CD44 that increased modestly after incubation with IL-2. No cha nges in isoform expression in the extracellular domain of CD44 could b e detected upon activation with the use of isoform-specific mAbs. Thus , lymphokine stimulation caused CD44 to become a cytotoxic trigger in subsets of PBL that mediated other forms of cytotoxicity and expressed CD44 before activation, suggesting that activation of these cells was accompanied by a coupling of CD44 to their lytic machinery.