Reactivation of Toxoplasma gondii is a life threatening condition in patients with acquired immuno deficiencies that affect T cell function. This food and water borne parasite can also cause severe disease in immune-competent individuals and is classified as a class B biodefence pathogen. While previous work has established the important role of CD4+ and CD8+ T cells in resistance to T. gondii it still remains unclear which accessory populations are involved in the innate events required for the development of these protective responses. The ability of dendritic cells (DCs) to sense and respond differentially to distinct classes of pathogens, combined with their capacity to efficiently sample and present antigen to T lymphocytes makes these cells prime candidates for this task. Current models suggest that conventional myeloid and lymphoid DC (cDC) contribute to the development of resistance to T. gondii through the presentation of parasite derived peptides and the release of IL-12 that promotes the production of IFN gamma by NK and T cells. However, using mice in which only cDC are capable of presenting class II restricted epitopes we found that these cells are not sufficient for normal CD4+ T cell responses during toxoplasmosis. Unexpectedly, parallel work identified plasmacytoid DC (pDC), a newly described DC subset, as a prominent cell type involved in the development of T helper cell responses to Toxoplasma-derived class II restricted antigens. Additional studies established that pDC produce IL-12 and type I IFNs in response to T. gondii and have an innate ability to kill this pathogen. Together, these findings have led to a model in which pDC have a significant role in the innate events that lead to the activation of NK and T cells during toxoplasmosis. To test this hypothesis, techniques that allow imaging of parasite-DC interactions in vivo will be combined with a variety of transgenic parasites and established molecular and immunological techniques to focus on how pDC recognize T. gondii and their contribution to the development of innate and adaptive mechanisms of resistance to this pathogen.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1-AR-I (M2))
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Wali, Tonu M
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University of Pennsylvania
Schools of Veterinary Medicine
United States
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