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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI071302-05
Application #
7805577
Study Section
Special Emphasis Panel (ZAI1-AR-I (M2))
Program Officer
Wali, Tonu M
Project Start
2006-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$479,946
Indirect Cost
Name
University of Pennsylvania
Department
Pathology
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Stumhofer, Jason S; Silver, Jonathan S; Hunter, Christopher A (2013) IL-21 is required for optimal antibody production and T cell responses during chronic Toxoplasma gondii infection. PLoS One 8:e62889
Jensen, Kirk D C; Hu, Kenneth; Whitmarsh, Ryan J et al. (2013) Toxoplasma gondii rhoptry 16 kinase promotes host resistance to oral infection and intestinal inflammation only in the context of the dense granule protein GRA15. Infect Immun 81:2156-67
Harris, John E; Harris, Tajie H; Weninger, Wolfgang et al. (2012) A mouse model of vitiligo with focused epidermal depigmentation requires IFN-ýý for autoreactive CD8ýýý T-cell accumulation in the skin. J Invest Dermatol 132:1869-76
Hall, Aisling O'Hara; Beiting, Daniel P; Tato, Cristina et al. (2012) The cytokines interleukin 27 and interferon-? promote distinct Treg cell populations required to limit infection-induced pathology. Immunity 37:511-23
Silver, Jonathan S; Stumhofer, Jason S; Passos, Sara et al. (2011) IL-6 mediates the susceptibility of glycoprotein 130 hypermorphs to Toxoplasma gondii. J Immunol 187:350-60
Ricart, Brendon G; John, Beena; Lee, Dooyoung et al. (2011) Dendritic cells distinguish individual chemokine signals through CCR7 and CXCR4. J Immunol 186:53-61
Gregg, Beth; Dzierszinski, Florence; Tait, Elia et al. (2011) Subcellular antigen location influences T-cell activation during acute infection with Toxoplasma gondii. PLoS One 6:e22936
Wojno, Elia D Tait; Hosken, Nancy; Stumhofer, Jason S et al. (2011) A role for IL-27 in limiting T regulatory cell populations. J Immunol 187:266-73
John, Beena; Ricart, Brendon; Tait Wojno, Elia D et al. (2011) Analysis of behavior and trafficking of dendritic cells within the brain during toxoplasmic encephalitis. PLoS Pathog 7:e1002246
John, Beena; Weninger, Wolfgang; Hunter, Christopher A (2010) Advances in imaging the innate and adaptive immune response to Toxoplasma gondii. Future Microbiol 5:1321-8

Showing the most recent 10 out of 17 publications