Recent vaccination attempts using different immunogens such as viral vectors, DNA or synthetic constructs expressing pre-erythrocytic malaria antigens or their T cell epitopes, have provided important new information regarding the protective role of these T cells. It was shown that mice immunized with different immunogens, including selected viral 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 mic. These studies and others have raised a number of important questions related to the induction of effector and memory CD8+ T cell responses which need to be answered in order to further advance the design and development of an effective malaria vaccine. 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 to identify the parameters which closely reflect the in vivo anti-parasite activity of effector and memory CD8+ T cells and characterize the optimal conditions to establish efficient effector and memory CD8+ T cell responses. We also propose to study the immuno-regulatory mechanisms controlling the in vivo induction and maintenance of effector and memory CD8+ T cell responses. Using transgenic mice expressing a T cell receptor specific for a CD8+ T cell epitope of the P. yoelii CS protein , recently generated in my laboratory, we will study the molecular and functional properties characterizing the differentiation of CD8+ T cells from naive to effector and memory cells. Other transgenic mice expressing a pertinent class I MHC only in hepatocytes, also recently generated in my laboratory, will be used to evaluate the role of hepatocytes in the induction/activation of effector and memory CD8+ T cells directed against P. yoelii liver stages. Finally we propose studies aimed at enhancing the magnitude and efficacy of effector and memory CD8+ T cell responses by immunization with double recombinant vaccinia viruses expressing the P. yoelii CS protein and cytokines known to exert important immunomodulatory effects on T cell responses.
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