The long-term goal of this renewal application is to determine how gamma/delta T cells and non-cytolytic alpha/beta T cells regulate tolerance to OVA as an exogenous antigen, an endogenous antigen and as a tumor antigen. Transgenic mice expressing OVA-specific TCR on CD8+ T cells (TCR-1) or CD4+ T cells (OT-11) and a variety of knockout mice will be used to explore the physiological signals that control development of tolerance.
The first aim i s to characterize non- cytolytic, CD8+ T cells from B6 mice expressing transgenic TCR-1 T cells and gamma/delta T cells cloned from intra-epithelial lymphocytes. Interactions between gamma/delta T cells and non- cytolytic, CD8+ T cells will be studied by adoptive transfer into gamma/delta TCR deficient mice. Recipients expressing transgenic, OT-11 T cells will be used to determine how non-cytolytic CD8+ T cells inhibit antibody responses. In the second aim, the function of gamma/delta T cells and non-cytolytic CD8+ T cells in OVA transgenic mice will be evaluated using TCR-1 mice. The hypothesis that E.G7-OVA induces tumor-specific tolerance will be tested in the third aim. If tolerance is found, the investigator will determine whether CD8+ T cells are deleted, anergic or display altered functions. The ability of E.G7-OVA tumors transfected with a co-stimulatory molecule to reverse tolerance will be tested. The cellular and molecular effects of noscapine on tumor-specific- tolerance and immunity will be identified. Results from these studies should provide the basis for developing clinical trials of noscapine in humans.
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