Early immunity to infectious agents generally involves a very well defined T cell response to a few immunodominant epitopes. However, the role of antigen specificity in T cell accumulation at chronic inflammatory sites is much less understood. The primary goal of this application is to understand the role of antigen and T cell receptor specificity in chronic granulomatous inflammatory reactions. This information is not presently available due to the technically challenging problem of tracing the low frequency T cells specific for a given antigen. T cell receptor transgenic animals and their respective antigens will be used to overcome this difficulty. This technology will help us to characterize the phenotype and function of T cells activated specifically by antigen or through alternative activation pathways within a localized inflammatory site. Our model will be one of granulomas induced by Leishmania chagasi donovani (LCD) where T cells are crucial for granuloma formation. T cell receptor transgenic mice with a T cell repertoire consisting only two different monospecific T cells will be infected with recombinant LCD expressing an epitope recognized by only one kind of the T cells. The localization and activation stages of these cells will be measured. The two transgenic T cell populations will be sorted and their capacity to control parasite load, form granulomas, and produce lymphokines will be tested in adoptive transfer studies. The experiments will be repeated in wild type adoptive transfer recipients to examine the function of the monospecific T cells within a normal population. These systems will be used to study the effects of immunization on cytokine and effector functions of specific and non-specific T cells. There are three Specific Aims for our application. First, we will determine the proportion of antigen-specific and unrelated antigen restricted T cells in granulomas and in the immune periphery during infection.
(Aim 1). Next, we will study the functional role and characteristics of these defined populations throughout the parasitic infection (Aim 2). Finally, we will use vaccination to modify the T cells, activated specifically by antigen or through alternative activation pathways in the granulomas in order to design new, precisely targeted therapies for T cell functions in parasitic diseases (Aim 3). We believe that the successful completion of this research project will lead to an improved understanding of the role of T cells in granulomatous diseases and thus provide the foundation for new therapeutic methodologies for controlling granulomatous inflammatory diseases, such as leishmaniasis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI048087-05
Application #
6752884
Study Section
Immunological Sciences Study Section (IMS)
Program Officer
Johnson, David R
Project Start
2000-07-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2006-05-31
Support Year
5
Fiscal Year
2004
Total Cost
$252,375
Indirect Cost
Name
University of Wisconsin Madison
Department
Pathology
Type
Schools of Medicine
DUNS #
161202122
City
Madison
State
WI
Country
United States
Zip Code
53715
Rayasam, Aditya; Kijak, Julie A; Dallmann, McKenna et al. (2018) Regional Distribution of CNS Antigens Differentially Determines T-Cell Mediated Neuroinflammation in a CX3CR1-Dependent Manner. J Neurosci 38:7058-7071
Harris, Melissa G; Hulseberg, Paul; Ling, Changying et al. (2014) Immune privilege of the CNS is not the consequence of limited antigen sampling. Sci Rep 4:4422
Clarkson, Benjamin D S; Ling, Changying; Shi, Yejie et al. (2014) T cell-derived interleukin (IL)-21 promotes brain injury following stroke in mice. J Exp Med 211:595-604
Schreiber, H A; Harding, J S; Altamirano, C J et al. (2011) CONTINUOUS REPOPULATION OF LYMPHOCYTE SUBSETS IN TRANSPLANTED MYCOBACTERIAL GRANULOMAS. Eur J Microbiol Immunol (Bp) 1:59-69
Schreiber, Heidi A; Sandor, Matyas (2010) The role of dendritic cells in mycobacterium-induced granulomas. Immunol Lett 130:26-31
Hogan, Laura H; Co, Dominic O; Karman, Jozsef et al. (2007) Virally activated CD8 T cells home to Mycobacterium bovis BCG-induced granulomas but enhance antimycobacterial protection only in immunodeficient mice. Infect Immun 75:1154-66
Hogan, Laura H; Heninger, Erika; Elsner, Rebecca A et al. (2007) Requirements for CD4(+) T cell levels in acute Mycobacterium bovis strain bacille Calmette Guerin (BCG)-induced granulomas differ for optimal mycobacterial control versus granuloma formation. Int Immunol 19:627-33
Heninger, Erika; Hogan, Laura H; Karman, Jozsef et al. (2006) Characterization of the Histoplasma capsulatum-induced granuloma. J Immunol 177:3303-13
Co, Dominic O; Hogan, Laura H; Karman, Jozsef et al. (2006) Interactions between T cells responding to concurrent mycobacterial and influenza infections. J Immunol 177:8456-65
Co, Dominic O; Hogan, Laura H; Il-Kim, Shin et al. (2004) T cell contributions to the different phases of granuloma formation. Immunol Lett 92:135-42

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