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, and recombinant viral vectors as well as synthetic constructs such as DNA, have provided important new information regarding the protective role of these T cells. Our recent studies on CD8+ T cell responses against the CS protein of P. yoelii established that when sporozoites are delivered by mosquito bites, the T cell response is induced by dendritic cells (DCs) in skin draining lymph nodes (LN). Primed cells migrate to peripheral organs including the liver, where they develop memory CD8+ populations. Upon challenge these liver resident CD8+ T cells are able to eliminate malaria infection. To protect, T cells have to see antigen in the context of liver parenchymal cells - presumably infected hepatocytes - and need not be re-stimulated by bone-marrow derived DCs. Thus the processes of priming the CD8+ T cell response and eliciting effector function from those cells involve different cellular and molecular interactions. 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. These studies aim to define basic features of the key initial interactions that occur between sporozoites, DCs and pattern recognition receptors which lead to the acquisition and presentation of parasite antigen to CD8+ T cells in LN. We also propose studies on liver-resident memory CD8 cells which aim at characterizing the mechanisms that mediate their homing to the liver, at defining their functional properties and evaluating conditions that may modulate the permanence and anti-parasite activity of these memory cells. These studies will be facilitated by the availability of TCR transgenic mice and transgenic parasites expressing model CD8 epitopes developed in my laboratory. These enable us to track CD8 T cells throughout their differentiation in both normal and gene-knockout animals. Finally, we will develop research aimed at studying the functional properties and evolution of memory responses against the P. yoelii CS protein. We will evaluate the fate of these memory cells under continued antigen stimulation which normally occurs due to repeated parasite exposure and antigen persistence. We will study the renewal mechanisms of memory populations and the relationship between different memory cell subsets i.e., those residing in the liver (effector memory and those from lymph nodes (central memory).
The proposal aims at investigating basic features of CD8+ T cell responses against Malaria liver stages. We propose to characterize the role of dendritic cell subsets in induction of this response, the role of adhesion molecule in homing and functional properties of liver-resident anti-Malaria memory T cells and study the mechanisms controlling the evolution and maintenance of protective memory CD8+ T cells.
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|Espinosa, Diego A; Radtke, Andrea J; Zavala, Fidel (2016) Development and Assessment of Transgenic Rodent Parasites for the Preclinical Evaluation of Malaria Vaccines. Methods Mol Biol 1403:583-601|
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|Luo, Kun; Zhang, Hong; Zavala, Fidel et al. (2014) Fusion of antigen to a dendritic cell targeting chemokine combined with adjuvant yields a malaria DNA vaccine with enhanced protective capabilities. PLoS One 9:e90413|
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