Although it is clear that NK cells can kill a subpopulation of activated CD4 T cells, the defining characteristics of this target population from an NK cell point-of-view are unknown. Moreover, work from other labs has suggested that macrophages, dendritic cells, CD8 T cells, and even B cells may be potential targets of NK cells. In addition to sorting out the physiological relevance of these target cell populations in our virus infection model systems, we aim to determine the receptor-ligand interactions that control this killing activity. The cytolytic function of NK cells is dictated by the net signaling input of a variety of activating and inhibitory cell surface receptors. There is a need to carefully evaluate the expression of NK cell receptors, their ligands, and associated adaptor proteins at various times after infection. Thereafter, we can examine which pathway or changes in protein expression are required for NK cell lytic function in this immunoregulatory capacity. These studies currently involve projects centered on the identification of a ligand for an activating receptor that might be up-regulated on activated cells to make them susceptible to NK cell lysis. Further, a separate project has focused on changes in inhibitory receptor ligand expression which may imbue certain subpopulations of lymphocytes with resistance to NK cell killing.