ALPHA-CHEMOKINE AND BETA-CHEMOKINE INDUCE NK CELL-MIGRATION AND ENHANCE NK-MEDIATED CYTOLYSIS

Chemokines have been shown to play an important role in both the adhes ion and migration of numerous leukocytic cell types, including granulo cytes, monocytes, mast cells, and T lymphocytes. However, the biologic effects of chemokines on NK cells remain to be defined. Chemotaxis st udies using purified human NK cells and a panel of human recombinant c hemokines revealed that macrophage inflammatory protein (MIP)-1 alpha and IFN-inducible protein-10 (IP-10) are potent NK cell chemoattractan ts in vitro. Modest but significant chemotactic (not chemokinetic) res ponses were also observed in response to RANTES, MCP-1, MCP-2, MCP-3, and MIP-1 beta. Chemokine receptor expression on human NK cells was de termined through displacement and Scatchard analyses, using a panel of radiolabeled chemokines, and revealed the presence of both distinct a nd shared chemokine receptors with affinities similar to those previou sly described for other cell types. Functional studies have also revea led that the beta chemokines and IP-10 are capable of augmenting NK- b ut not LAK- or ADCC-specific cytolytic responses in both a dose- and d onor-dependent fashion. Neutralization analysis using Abs specific for various adhesion molecules revealed that NK:tumor cell conjugate form ation is required for chemokine-induced NK killing. In addition; NK ce lls incubated in the presence of beta chemokines and IP-10 for 4 h ind uced the release of granule-derived serine esterases, suggesting a pos sible mechanism for chemokine-mediated NK killing. These results sugge st that chemokines not only play an important role in the recruitment of NK cells, but also may be important mediators of NK cell degranulat ion augmenting local tumor cell destruction.