The broad objective of this project 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 b chain of an MHC class II, I-Ek molecule. APC from these mice are recognized by cytochrome-specific, I-Ek 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 transferred into 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. Antigen-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. 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 do not induce T cell proliferation, but enable T cells to survive and remain responsive to antigen will be compared.

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 #
5R37AI029544-12
Application #
6341609
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Quill, Helen R
Project Start
1991-01-01
Project End
2003-12-30
Budget Start
2001-01-01
Budget End
2001-12-31
Support Year
12
Fiscal Year
2001
Total Cost
$183,529
Indirect Cost
Name
Oregon Health and Science University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009584210
City
Portland
State
OR
Country
United States
Zip Code
97239
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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
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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