Apicomplexan parasites are responsible for a number of human diseases, including toxoplasmosis, cryptosporidiosis, and malaria, and efforts to develop vaccines and therapeutics against these invaders are hampered by our lack of understanding of how T cell responses to parasites are generated and maintained. In the past funding period of this grant, we have characterized a remarkably potent, naturally occurring CD8 T cell response directed against a parasite protein Gra6, and have shown that T cells with this specificity are expanded rapidly and maintained as a potent effector/memory population long after establishment of a latent infection. In the current application, we will test the hypothesis that the spatial and temporal pattern of presentation of parasite antigens to CD8 T cells is key to generating a potent and sustained effector T cell response, and to allowing effector T cells to deliver effector molecules where they can provide maximum protection with minimal collateral damage.
In Aim 1 we will probe the mechanisms that account for the rapid priming and robust maintenance of this response (Aim 1a), will examine the impact of regulated secretion of the antigen in determining the efficacy of the resulting CD8 T cell response (Aim 1b), and will explore the division of labor between distinct subsets of Gra6 specific T cells (Aim 1c).
In Aim 2 we will examine the relationship between T cell protection and the ability to deliver effector molecules directly to invaded host cells while avoiding damage to non-invaded host cells. The successful completion of these aims will expand our ability to recognize and generate effective CD8 T cell responses, and thus will improve our ability to develop effective treatments against intracellular parasites.
Toxoplasma gondii is a parasite that causes birth defects or brain infection in immunocompromised adults. We are using a mouse infection model and advanced microscopy methods to gain a better understanding of how the immune system protects against the parasite and how the parasite attempts to evade the immune system. The Toxoplasma-mouse infection model is also relevant for how the mammalian immune system protects against the related intracellular protozoan parasites, Plasmodium and Cryptosporidium. Thus, these studies have relevance for the development of therapeutic strategies against a variety of dangerous pathogens.
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