Tumors are known for providing T cells with poor costimulatory environments for T cell activation, making T cell anergy, ignorance, and """"""""exhaustion"""""""" to tumors well-documented phenomena. Previously, it has not been possible to accurately assess the specific role of TCR-dependent activation-induced T cell death (AICD) in determining whether T cell tolerance or immunity to tumors prevails. This is because a means of specifically blocking the death signal from the TCR has not been available. We have generated a mutation in the TCR beta-chain constant region (bTM-g) which imparts wild-type T cell proliferation but resistance to AICD to antigen-stimulated T cells in transgenic mice. The specific resistance of bTM-g T cells to TCR-dependent AICD will be very useful in determining the role this pathway normally plays in determining peripheral immune responses to tumors.
Specific Aims : (1) Identify the death-signaling pathway(s) that is(are) directly inhibited by the bTM-g mutation. (2) Determine the role of TCR-dependent AICD in the development of tumor immunity. We believe the bTM-g model will be immediately useful in clarifying the role of TCR-dependent AICD in maximizing immunity and escape from tolerance to tumors. We hypothesize that the ability to specifically inhibit TCR-dependent AICD will reveal that this process normally plays a role in downregulating anti-tumor immune responses. We further propose that the bTM-g mutation may spotlight an important motif which could be targeted pharmacologically.
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