This research project is based on the hypothesis that B lymphocytes are tolerogenic antigen presenting cells (APC): when B cells present antigen to naive helper T cells, they turn them off instead of on because they lack certain costimulatory signals required by the T cells. The proposed experiments address the following questions: (1) Are B cells important APC in classical models of acquired tolerance to protein antigens? B cell deficient mice (mMT/mMT knockout) will be compared to normal mice in classical high and low-zone tolerance protocols. (2) Do B cells act as self antigen-specific APC to induce tolerance to soluble self antigens? The frequency of self-reactive T cells to a soluble, low-concentration self antigen (hen egg lysozyme expressed from a transgene) will be compared in B cell knockout mice and normal mice. (3) In the current grant period, it has been shown that transfer of B cells expressing a transgene- encoded membrane protein induces tolerance to the protein. How do the rules change when the B cells are activated or when T cells are primed? Are the rules the same for CD4+ and CD8+ T cells? How does constitutive expression of B7 affect tolerance induction by B cells in vivo? (4) What happens to naive T cells when they see antigen on B cells? Peptide antigen conjugates of Fab fragments of anti-IgD will be used to target antigen to B cells. T cell antigen receptor transgenic mice specific for the peptide antigen will be used as a source of otherwise rare, naive, antigen- specific T cells for studies on tolerance induction in vivo and interactions with antigen presenting B cells in vitro. Health relatedness: Acquired tolerance is a model for peripheral self tolerance, since both phenomena require inactivation of mature, immunocompetent lymphocytes. A failure of self tolerance in the periphery is a likely cause of autoimmune disease. Pathogenic autoantibody production may result from helper T cell recognition of self antigens presented by B cells. Acquired tolerance induced by B cells as APC could also be relevant to transplantation, allergy, the effective use of novel therapeutic proteins, tumor immunity, and chronic infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
7R01AI029544-05
Application #
2065045
Study Section
Immunobiology Study Section (IMB)
Project Start
1991-01-01
Project End
1998-12-31
Budget Start
1994-10-05
Budget End
1994-12-31
Support Year
5
Fiscal Year
1994
Total Cost
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
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
Evans, D E; Munks, M W; Purkerson, J M et al. (2000) Resting B lymphocytes as APC for naive T lymphocytes: dependence on CD40 ligand/CD40. J Immunol 164:688-97
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 (1993) Parameters of tolerance induction by antigen targeted to B lymphocytes. J Immunol 151:2958-64

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