Ligation of CD8α on human natural killer cells prevents activation-induced apoptosis and enhances cytolytic activity

It has been previously shown that the subset of human natural killer (NK) cells which express CD8 in a homodimeric alpha/alpha form are more cytotoxic than their CD8(-) counterparts but the mechanisms behind this differential cytolytic activity remained unknown. Target cell lysis by CD8(-) NK cells is associated with high levels of effector cell apoptosis, which is in contrast to the significantly lower levels found in the CD8 alpha(+) cells after lysis of the same targets. We report that cross-linking of the CD8 alpha chains on NK cells induces rapid rises in intracellular Ca(2+) and increased expression of CD69 at the cell surface by initiating the influx of extracellular Ca(2+) ions. We demonstrate that secretion of cytolytic enzymes initiates NK-cell apoptosis from which CD8 alpha(+) NK cells are protected by an influx of exogenous calcium following ligation of CD8 on the NK-cell surface. This ligation is through interaction with fellow NK cells in the cell conjugate and can occur when the target cells lack major histocompatibility complex (MHC) Class I expression. Protection from apoptosis is blocked by preincubation of the NK cells with anti-MHC Class I antibody. Thus, in contrast to the CD8(-) subset, CD8 alpha(+) NK cells are capable of sequential lysis of multiple target cells.