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By
From the Departments of Medicine, Surgery, Anatomy, and Cell Biology and the Transplantation
Immunology and Immunogenetics Laboratories, State University of New York Health Science Center at
Brooklyn, Brooklyn, New York 11203
A receptor-ligand interaction exclusive to natural killer (NK) cell-mediated recognition and
triggering of tumor cell destruction has not yet been identified. In contrast, molecules that are
involved in cellular adhesion and regulation of NK cytolysis have been well studied. In this report, a novel tumor surface protein is identified that exhibits characteristics of a recognition
structure for naive NK cells. A tagged ligand-cell adsorption technique revealed a 38.5-kD
plasma membrane protein (p38.5) from a prototypical NK-susceptible cell line (K562) that preferentially bound to NK cells (CD3
CD5CD16+) relative to T lymphocytes (CD3+CD5+
CD16). The molecule was purified to apparent homogeneity for further characterization. An
amino acid sequence of an 11-mer internal peptide of p38.5 did not exhibit homology to
known proteins. Affinity-purified antibody generated against this peptide (anti-p38.5) reacted
with a single protein of 38.5 kD on Western blots of whole cell extracts of K562. Flow cytometry and immunoprecipitation studies of surface-labeled tumor cells demonstrated expression of
p38.5 on NK-susceptible tumor cell lines (K562, MOLT-4, Jurkat), whereas p38.5 was not detected on NK-resistant tumor cell lines (A549, Raji, MDA-MB-231). Significantly, p38.5 loss
variants derived from wild-type Jurkat and Molt-4 cell lines exhibited decreased susceptibility
to NK cell-mediated lysis demonstrating a strong association between cell surface expression of
p38.5 and cytotoxicity. Purified p38.5 retained preferential binding to NK cells and inhibited
NK activity in a dose-dependent manner, thereby providing direct evidence of a role in the
lytic process. Binding studies identified a 70-kD membrane protein from NK cells as a possible
receptor for the p38.5 tumor ligand. Consistent with cellular adsorption studies, the 70-kD,
p38.5 binding protein was not detected on T lymphocytes. Based on studies demonstrating selective binding of p38.5 to NK cells, lack of expression on NK-resistant tumor cell lines and ability of the purified molecule to block cytolysis, we conclude that p38.5 may serve as a recognition/triggering ligand for naive human NK cells.
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