Infusion of ex vivo activated killer cells is currently a popular modality of immunotherapy, especially for the treatment of cancer. A significant proportion of the cells are activated by rIL-2, and are termed lymphokine activated killer (LAK) cells. The predominant cellular precursor of LAK cells are natural killer (NK) cells. We have continued our ongoing interest in NK cell biology. The mechanism by which LAK cells acquire a broader lytic capacity than their precursors, NK cells, is poorly understood. LFA-1 has been shown to function for adhesion of NK and LAK effector cells to their target cells. It is a member of a superfamily of adhesion molecules consisting of covalently linked heterodimers containing unique ` chains (CDlla for LFA- 1) and a common beta chain (CD18). Based on published evidence and our own observations, we generated and explored the hypothesis that utilization of an LFA-1 signal transduction pathway functionally distinguishes human LAK from NK cells. Using NK cells isolated by negative selection with monoclonal antibodies (90% CD16-positive), we found that antibodies to the LFA-1 beta chain strongly inhibited LAK activity while only moderately suppressing NK activity, suggesting a differential role for LFA-1 beta in LAK compared to NK mediated lysis. LFA-1 beta was strongly phosphorylated in LAK but not NK cells and immunoprecipitated with another phosphoprotein (85-90 kDa). Crosslinking of the LFA-1 beta chain stimulated calcium-dependent release of cytoplasmic granules containing lytic molecules and induced phosphatidyl inositol turnover in LAK but not NK cells. We concluded that the IL-2- induced phosphorylation of the LFA-1 beta chain in LAK cells and associated alteration in signal transduction, may represent an important functional distinction between NK and LAK cells. In a satellite collaborative project, remaining from the PI's previous UCLA association, we reported that NK activity is modulated in vivo during stress. This modulation was more pronounced among young than old subjects.
