EXCEED THE SPACE PROVIDED. The broad objective is to understand the conditions which determine whether an antigen-specific interaction between T and B cells results in immunity or tolerance. Work supported by this grant has shown that B cells are tolerogenic antigen presenting cells in vivo. The general strategy for the proposed grant period is to use TCR transgenic T cells to circumvent the low frequency of naive, antigen-specific T cells in normal animals, and so gain direct access to antigen-specific, tolerizing cellular interactions in vivo and in vitro. Antigen- transgenic mice have been made that express a cytochrome c peptide analog covalently attached to the p chain of an MHC class II, I-E^ molecule. APC from these mice are recognized by cytochrome-specific, 1-E^ restricted T cells of the AND strain of T cell antigen receptor (TCR) transgenic mice. Resting or activated antigen- transgenic B cells or other APC will be transferredinto mice with circulating primed or naive TCR transgenic T cells, and TCR transgenic T cells will be transferred into mice in which antigen is presented only on B cells or on other types of APC. The fate and phenotype of the T cells will be followed by flow cytometry, and their functional capabilities will be studied by secondary challenge with antigen in vitro. Anugen-transgenic mice will be bred to CD40 deficient and B7-1 transgenic mice to study the roles of those molecules in T/B interactions in vivo. We will also compare the functional consequences for naive T cells of an initial encounter in vitro with antigen on resting normal B cells (which induces T cell proliferation) and resting, CD40-deficient B cells, which does not induce T cell proliferation, but enables T cells to survive and remain responsive to antigen. PERFORMANCE SITE ========================================Section End===========================================

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI029544-16
Application #
6845091
Study Section
Special Emphasis Panel (NSS)
Program Officer
Nabavi, Nasrin N
Project Start
1991-01-01
Project End
2006-12-31
Budget Start
2005-01-01
Budget End
2006-12-31
Support Year
16
Fiscal Year
2005
Total Cost
$264,250
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Koguchi, Yoshinobu; Thauland, Timothy J; Slifka, Mark K et al. (2007) Preformed CD40 ligand exists in secretory lysosomes in effector and memory CD4+ T cells and is quickly expressed on the cell surface in an antigen-specific manner. Blood 110:2520-7
Wetzel, Scott A; Parker, David C (2006) MHC transfer from APC to T cells following antigen recognition. Crit Rev Immunol 26:1-21
Dullforce, Per A; Seitz, Greg W; Garman, Kiera L et al. (2006) Antigen-specific accumulation of naive, memory and effector CD4 T cells during anterior uveitis monitored by intravital microscopy. Cell Immunol 239:49-60
Wetzel, Scott A; McKeithan, Timothy W; Parker, David C (2005) Peptide-specific intercellular transfer of MHC class II to CD4+ T cells directly from the immunological synapse upon cellular dissociation. J Immunol 174:80-9
Wetzel, Scott A; McKeithan, Timothy W; Parker, David C (2002) Live-cell dynamics and the role of costimulation in immunological synapse formation. J Immunol 169:6092-101
Baird, A M; Parker, D C (1996) Analysis of low zone tolerance induction in normal and B cell-deficient mice. J Immunol 157:1833-9
Yuschenkoff, V N; Sethna, M P; Freeman, G J et al. (1996) Coexpression of B7-1 and antigen blocks tolerance induction to antigen presented by resting B cells. J Immunol 157:1987-95
Lalmanach-Girard, A C; Chiles, T C; Parker, D C et al. (1993) T cell-dependent induction of NF-kappa B in B cells. J Exp Med 177:1215-9
Eynon, E E; Parker, D C (1992) Small B cells as antigen-presenting cells in the induction of tolerance to soluble protein antigens. J Exp Med 175:131-8