Understanding the mechanisms which determine whether engagement of the T- cell receptor leads to clonal expansion or death remains a major goal in immunology. During the last grant period, we discovered a novel member of the Bcl-x family which may play a central role in this process. Bcl-xgamma is selectively expressed in T-cells after a splicing event associated with TCR ligation by not after other forms of T-cell activation. Expression of this intracellular protein appears to be essential for survival of T-cells and failure to express Bcl-xgamma is a reliable predictor of apoptosis and deletion. The tight coupling of Bcl-xgamma expression to TCR ligation may represent a mechanism for conversion of the interaction between peptide ligands and the TCR into successful activation and/or positive selection. According to this view, insight into the receptor/ co-receptor signals leading to Bcl-xgamma expression should establish the physiologic role of this gene in T-cell development. These considerations also suggest that dysregulated expression of Bxl-xgamma might lead to excessive T-cell growth and autoimmune disease. Our preliminary observations that DN cells from MRL/1pr mice constitutively express Bcl-xgamma but not Bcl-xgamma and enforced expression of a Bcl-xgamma transgene leads to expansion of DN cells are consistent with this hypothesis.
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