: CD8+ T cells play a major protective role in immunity to malaria infection by inhibiting the development of liver stages. Vaccination studies using malaria sporozoites as well as viral vectors, DNA or synthetic constructs expressing malaria antigens have provided important new information regarding the protective role of these T cells. It was shown that mice immunized with different vectors expressing the same plasmodial sequence induce malaria-specific CD8+ T cells, which strongly inhibit liver stage development, conferring sterile immunity to a significant proportion of the immunized mice. More recently, we demonstrated that the induction of these T cell responses fully depends on IL-4 secreting CD4+ T cells. These studies have raised a number of important questions with regard to the nature of the factors mediating CD4+/CD8+ T cell cross talk and to the mechanisms which regulate the induction and development of effector and memory CD8+ T cell responses. We propose to undertake studies aimed at characterizing some basic aspects of the in vivo CD8+ T cell responses against the liver stages of P. yoelii. We propose investigations aimed at defining basic parameters of CD4+/CD8+ T cell cross talk and identifying the cellular and molecular mechanisms underlying the helper effect of CD4+ T cells. We also propose to characterize the recall memory CDS+ T cell responses with regard to the effector mechanisms used by memory cells to inhibit parasite development and the regulatory mechanisms that control the in vivo expansion of memory CD8+ T cells, upon reencounter with parasite antigen. For these studies, we have generated transgenic mice expressing a T cell receptor specific for a CD8+ T cell epitope and another expressing a TCR specific for a CD4+ T cell epitope. Both epitopes are recognized by T cells that inhibit parasite development and are located in the P. yoelii CS protein. The availability of these TCR transgenic mice will allow the use of large numbers of monoclonal T cell populations for in vivo studies, greatly facilitating the characterization of functional and molecular properties of T cells before and after encountering parasite antigen, and through the differentiation process from activated to memory T cells.
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