: - In addition to being a complete carcinogen, exposure to ultraviolet (UV) radiation is immunosuppressive. Studies with both experimental animals and biopsy proven skin cancer patients have indicated that the immune suppression induced by UV radiation is a major risk factor for skin cancer development. Exposing mice to subcarcinogenic doses of UV suppresses their immune response and allows for the outgrowth of UV-induced skin cancers. This immune suppression can be transferred to normal recipients by adoptive transfer of splenic CD3+, CD4+, CD8- suppressor T cells (UV-Ts), cells that are also responsible for controlling the induction of the primary tumor in the UV-irradiated host. One glaring gap in our knowledge of the mechanism(s) by which UV exposure suppresses tumor immunity is the incomplete understanding of the exact identity and function of UV-Ts. Previous studies from this laboratory indicate that one mechanism by which UV-Ts down-regulate immunity is by interleukin (IL)-2 secretion. According to current immunological literature, only two T cell subsets readily secrete IL-4, T heIper-2 cells, and natural killer T (NKT) cells. Because of unique surface markers on NKT cells, it is possible to separate T helper-2 cells from NKT cells. Our preliminary findings indicate that a highly purified population of NK1 cells can transfer suppression of tumor immunity from UV-irradiated mice to normal recipients. The focus of this grant proposal is to test the hypothesis that UV-Ts are NKT cells. The specific alms of this grant are designed to answer the following questions: 1) Are UV-Ts NKT cells? 2) How do NKT cells suppress tumor rejection? 3) Is the activation of UV-induced NKT cells CD1 restricted? 4) How does the altered cytokine environment found in UV-irradiated mice affect the induction/activation of NKT cells? 5) Is it possible to clone NKT cells with suppressive activity from the lymphoid organs of UV-irradiated mice? The long-term goal of this research is to determine how UV exposure induces systemic immune suppression and permits the outgrowth of skin cancer. Because there is a link between the ability of UV exposure to suppress immunity and induce skin cancer, it is critically important to understand how these immune regulatory cells function to suppress immunity and promote cancer development. A better understanding of the mechanisms involved in UV-induced immune suppression may help with the design of rational approaches to block immune suppression, thereby reducing one of the major risk factors for skin cancer induction.