CD44 IS A CYTOTOXIC TRIGGERING MOLECULE ON HUMAN POLYMORPHONUCLEAR CELLS

In this study, we present evidence that CD44 is a cytotoxic triggering molecule on freshly isolated polymorphonuclear cells (PMN). PMN const itutively express high levels of CD44 as determined by FAGS analysis, and immunoprecipitation studies using PMN lysates and an anti-CD44 mAb show a band of 80 to 90 kDa that migrates slightly faster than CD44 f rom PBL. A bispecific Ab consisting of anti-CD44 Fab cross-linked to a nti-DNP Fab (anti-CD44(Fab) x anti-DNP(Fab)) induces PMN to lyse DNP-c oated tumor cells in an 18-h assay, and this lysis is specifically inh ibited by a polyclonal anti-CD44 F(ab')(2). A second bispecific Ab, an ti-CD16(Fab) x anti-DNP(Fab), that binds to Fc gamma RIIIb on PMN does not induce lysis, indicating that the bridging of target cells to PMN per se is not sufficient for killing. Moreover, CD44-directed killing by PMN results in the lysis of bystander cells, suggesting that the m echanisms of tumor cytolysis by CD44-targeted PMN does not require cel l-cell contact. Lastly, PMN lyse target cells coated with hyaluronic a cid (HA), the principal ligand for CD44, and this cytolytic activity i s specifically blocked by the polyclonal anti-CD44 F(ab')(2) and by an anti-CD44 mAb. We suggest that the interaction of HA with CD44 on neu trophils might initiate cytotoxic or inflammatory responses in vivo wh en neutrophils encounter high amounts of HA, for example on tumor cell s, or in the extracellular matrix.