LIVER MEMORY CD8 T CELLS IN PROTECTION TO MALARIA

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DESCRIPTION (provided by applicant): Memory T cells are one of the cardinal features of antigen-specific immune responses elicited by infections or vaccinations. The persistence of antigen-specific memory T cells is inextricably linked to long-lasting protection because they can be recalled into a swift effector function, hence their importance in prophylactic immunization against pathogens. The long-term goal of this proposal is to gain insights into the mechanisms of maintenance and a recall of memory CDS T cells, considered the main effectors against pre-erythrocytic stage malaria infection. The mouse model of sterile and lasting protection induced by radiation-attenuated Plasmodium berghei sporozoites is an excellent system for addressing the issues surrounding memory CDS T cells. Our hypothesis is that protracted protection induced by attenuated sporozoites depends in part on a network of liver memory CDS T cell subsets, each representing a different phase of activation or differentiation, the balance of which is profoundly affected by the repository of liver-stage antigens and cytokines. The specific aims are: (1) To identify liver cells that contain the repository of liver-stage antigens for the maintenance of memory CDS T cells. The localization of radiation-attenuated P. berghei parasites in the liver will be determined by the use of green fluorescence protein-parasites in combination with flow cytometry, confocal and electron microscopy. Liver and spleen cells will be tested for their role as antigen presenting cells. Mouse strains with specific genetic defects, such as the absence of certain cytokine or disrupted antigen processing pathway, will be used to confirm the antigen processing and presentation mechanisms. (2) To elucidate mechanisms of antigen presentation for recall and/or maintenance of liver memory CDS T cells. These studies will be conducted in vivo and in vitro and will focus on the identification of the antigen presenting cells, co-stimulatory molecules, CD27:CD70, CD40:CD40L, and 1- 4BB:1-4BBL, as well as cytokines, IL-7 and IL-15, that are needed to maintain memory CDS T cells. The results from these investigations will significantly enhance our understanding of memory CDS T cell response, which is a key element for consideration in the development of vaccines to prevent or abate malaria and other infectious diseases.