Hybrid and allogeneic resistance to bone marrow allografts in irradiated mice is an H-2 specific reaction against Hemopoietic histocompatibility (Hh) antigens. Natural Killer (NK) cells mediate this rejection phenomenon, and in doing so may utilize Hh-specific receptors. This offers the opportunity to investigate the nature of antigen specific receptors on NK cells, a cell type extremely important in surveillance against tumor cells. The nature of immunoglobulin receptors on B cells and T cell receptors have been well studied and characterized; if receptors are discovered on NK cells, analysis of a third-type of lymphocyte receptor may be possible. However, one must first determine whether or not marrow graft rejection is mediated by circulating 'natural antibodies' (Aim 1). In vivo and in vitro anti-Hh reactions will be assessed, using marrow graft rejection, lysis of Hh+ and Hh- tumor cells by purified NK cells and inhibition of marrow colony-formation in vitro by NK cells, with or without serum present. We will secrete for NK cells with specificity for Hh antigens, using adsorption to monolayers of tumor cells expressing NK target structures but perhaps no Hh antigens, and vice versa. NK cells specific for Hh antigens will be expanded and cloned. Antibodies to these receptors will be sought (Aim 2). T suppressor cells capable of inhibiting hybrid resistance in a specific fashion have been described. We will attempt to detect, characterize, clone and expand such cells and test for anti-Hh receptors (Aim 3). Finally, we will assess the role of interferons, IL-2 and other cytokines in the mechanism of marrow allograft rejection; the key target cell probably is the NK cell (Aim 4).