Lymphocytes can be induced to mediate cytotoxic reactions against a variety of target cells by in vitro manipulations. These reactions can be against either NK-sensitive target cells (""""""""NK-like"""""""" or """"""""anomalous"""""""" killing) or against NK-resistant targets (""""""""lymphokine activated killing""""""""). Cytotoxic reactivity can be induced with various stimuli including mixed lymphocyte culture or interleukin-2 (IL-2). These types of cytotoxicity bear a number of similarities with natural killer (NK) cell mediated cytotoxicity, although some features such as the spectrum of target cells killed are quite different. We propose to investigate the similarities between these types of cellular cytotoxicity basing our studies on the hypothesis that LAK and NK are of the same lineage, are regulated similarly, and recognize the same target structures. The ideal means to study the development of these effector cells would allow for the induction of cytotoxicity from non-cytotoxic precursors. We have developed two such precursor systems; the induction of cytotoxicity with IL-2 from naturally NK-inactive human thymocytes and IL-2 stimulation of peripheral blood lymphocytes depleted of NK cells with the toxic lysosomotropic drug L-leucine methyl ester. The phenotype of cells capable of developing cytotoxic reactivity, the sequence of signals that must be delivered to these cells to develop cytotoxic function, and the specificity of the induced cytotoxicity will be studied. The effects of adherent cells and adherent cell products on the in vitro development of cytotoxicity will be studied. We have demonstrated the existance of suppressor cells for NK effector function and for the acquisition of the IL-2 and transferrin receptors. These cells will be characterized and their mode of action determined. The specificity of LAK and NK cells will be compared by immunoselection of target cells with LAK or NK effector cells and comparing the sensitivity of the selected targets to these effector systems. By examining the similarities and differences between LAK and NK at the precursor, regulatory, and effector levels we expect to be able to determine the functional relationship between these cell types.
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