Natural killer T (NKT) cells, the least known population of T cells, represent a large proportion of the T cells present in the liver of mice and humans. Murine NKT cells express the NK marker (NK1.l) and, in most instances, a single invariant T cell receptor encoded by the Va14 and Ja281 gene segments. Most recently, a synthetic glycolipid, a-galactosylceramide (aGalCer), was shown to activate NKT cells in the context of CD1 molecules. My earlier studies demonstrated that aGalCer displayed a strong anti-parasitic effect, preventing mice from developing overt malaria infection by eliminating the parasite's liver stages. This anti-parasitic activity of aGalCer was found to be mediated by Va14 NKT cells, since Va14 NKT-deficient, as well as CD1-deficient mice, which also lack NKT cells, fail to develop protection against malaria upon aGalCer injection. More recently, our preliminary studies have shown that aGalCer enhances protective anti-malaria immunity elicited by immunization with irradiated sporozoites. These preliminary data further indicate that the insoluble fraction of extracts from Plasmodium yoelii blood stages activates liver lymphoid cells of wild type, but not of NKT-deficient, CD id-mutant mice. The overall aim of this research proposal is to further characterize and determine the role that NKT cells play in the immune response against malaria in mice. For this purpose, I plan to: 1) Define the nature of malaria-specific immune responses enhanced by aGalCer-activated NKT cells, and determine their time of persistence in malaria-immunized mice; 2) Determine the mechanisms by which aGalCer-activated NKT cells enhance protective anti-malaria immunity and the corresponding specific T cell responses; 3) Identify and characterize parasite-derived antigen(s) that activate NKT cells. These studies are expected to provide information on the link that NKT cells establish between natural and acquired immunity. Our findings might be applicable not only to malaria, but also to other intra-cellular microbial pathogens. Furthermore, since aGalCer not only stimulates murine but also human NKT cells, the knowledge obtained by our studies is expected to contribute to the understanding of the role of human NKT cells, and the design of novel, more efficient vaccines.