The Journal of Immunology, Vol 131, Issue 6 2705-2709, Copyright © 1983 by American Association of Immunologists
Studies on the mechanism of the human natural killer cell lethal hit: analysis of the mechanism of protease inhibition of the lethal hit
JC Hiserodt, L Britvan and SR Targan
The terminal killer cell-independent lysis (KCIL) stage of the human
natural killer (NK) lethal hit is blocked by the protease enzymes trypsin
(T), chymotrypsin (CT), and papain (P). The present studies analyze the
mechanism of inhibition of KCIL by these enzymes. The pretreatment of
effector PBL with T or CT but not P effectively reduced the ability of
these cells to mediate NK lysis. This was due at least in part to a reduced
ability of the treated NK cells to bind the NK target K562. Pretreatment of
K562 cells with T, CT, or P also abolished their ability to serve as
targets due to reduced binding ability. These same enzyme-pretreated target
cells, however, were unaffected in their ability to bind a natural killer
cell-derived cytolytic factor (NKCF) molecule(s), as determined by direct
NKCF absorption studies or by their ability to cold target compete for the
binding of NKCF to another NKCF-sensitive cell, the L929 fibroblast,
thereby indicating that the K562 "target antigen" and the NKCF-receptor are
independently expressed structures. Furthermore, NKCF activity, as measured
by its ability to kill either K562 or L929 cells, was sensitive to T and CT
but resistant to P. These studies indicate that various proteases inhibit
NK-KCIL by different mechanisms and suggest that the lethal hit is a
complex process. The ability of P to inhibit KCIL but not affect NKCF
activity or the target cell NKCF receptor implies that additional NK cell-
derived materials may be required in the lethal hit during direct NK
cell-mediated cytotoxicity. A model depicting a hypothetical molecular
mechanism for human NK cytolysis is presented and discussed.
