The hypothesis to be tested is that the production of natural killer (NK) cells is a dynamic developmental process analogous to the production of other myeloid and lymphoid lineages and is dependent upon the interactions of three components: NK lineage progenitor cells, stromal cells, and growth factors. The aims of this proposal are to develop the methods and cell lines necessary to analyze NK cell production and maturation in vitro and to use those methods to answer fundamental questions about the control of production of NK cells from their progenitors. Long and short term bone marrow cultures will be used to analyze the requirements for progenitor cells (obtained either from bone marrow by Percoll gradient centrifugation, positive and negative selection with antibodies or from established lines of progenitor cells), stromal cells (cultured whole bone marrow stroma or selected lines) and growth factors (IL-2, IL-3, IL-1, IL-4 and other factors (NK-CSF?) found in Con A supernatant. Limiting dilution assays will be used to assess the effects on NK lineage cells of the neutrophilia-inducing tumor CE1460 and the biological response modifiers AIPP (2-amino-5-iodo-6-phenyl-4-pyrimidinone) and OK-432 (a pharmaceutical preparation of Streptococcus pyogenes). Transforming oncogenes (ab1, myc, and myc/raf) will be used to infect selected populations of NK lineage cells to obtain immortalized lines of NK cells and their progenitors. The long range goal of these studies is to understand the roles of NK cells both as products and as regulators of hemopoiesis.