A fundamental understanding of the mechanisms involved in the processing of antigens and their presentation to cells of the immune system is critical to the design of new and more effective treatments against cancer and other diseases. Analyses of antigen processing, presentation and host defense have focused on studying pathways in which proteins are degraded into small peptides that are subsequently presented to the immune system. Recently, a novel pathway for antigen presentation to T cells by the major histocompatibility complex class I-like molecule, CD1, has been identified. CD1 molecules have been shown to present glycolipids, such as those derived from Mycobacterium species, rather than peptides, to T cells. Murine and human CD1d molecules are recognized by a novel subpopulation of T cells called NKT cells. NKT cells produce both Th1 and Th2 cytokines and appear to be important in regulating and/or mediating immune responses to pathogens, as well as to cancer. CD1 molecules are expressed on the surface of hematopoietic cells (e.g., T cells, B cells, macrophages) and are found on a number of T and B cell lymphomas and leukemias. Our hypothesis is that alterations in the natural glycolipid ligands bound to CD1 in hematopoietic tumor cells affect their recognition by NKT cells. To test this hypothesis, the following specific aims are proposed: 1. Assess the role of the intracellular trafficking and cell surface turnover of CD1 molecules in their recognition by NKT cells, 2. Determine the endogenous ligands in representative murine CD1+ T cell lymphoma and B cell leukemia cells, and 3. Analyze the in vitro and in vivo antitumor activity of NKT and NK cells against murine CD1+ hematopoietic tumor cells. Alterations in CD1-bound glycolipid antigens may play important roles in the ability of these tumors to evade the host's antitumor immune response. The proposed studies will also have wide-ranging applications in the development of novel treatments aimed not only at CD1 hematopoietic tumor cells, but also infectious diseases and autoimmunity.