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.
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