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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI013600-21
Application #
2765791
Study Section
Immunobiology Study Section (IMB)
Program Officer
Quill, Helen R
Project Start
1976-06-01
Project End
2003-11-30
Budget Start
1998-12-01
Budget End
1999-11-30
Support Year
21
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
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