The overall aim of this proposal is to understand how T cells survive Fas/tumor necrosis factor receptor (TNFR)-mediated apoptosis during the antigen-induced proliferation phase and how the same T cells become susceptible to the apoptosis at the end of the response. Antigen stimulation induces not only proliferation of T cells, but also the expression of molecules leading to cell death such as Fas, TNFR, and their ligands, Fas ligand (FasL) and TNFalpha. Binding of FasL and TNF-alpha to Fas and TNFR on activated T cells triggers a cell suicide program, which, however, occurs only at the end of the immune response. Under normal conditions, this ensures the elimination of unwanted, activated T cells, which, if left unchecked, can eventually lead to autoimmune disorders. It has generally been believed that in addition to Bcl-2 and Bcl-xL, two well- studied anti-death genes, the ability of the Fas+/TNFR+ T cells to proliferate at the early phase of immune response is primarily regulated by other as yet unidentified anti-death mechanisms. The applicant recently isolated a novel anti-death gene IEX-1L, that protects cells from Fas/TNFR-induced apoptosis. Its expression is rapidly induced by TNF-alpha stimulation through the activation of NF-kappaB/rel transcription factors, which renders the cells resistant to TNFR-induced cell death. The applicant hypothesizes that this may also be the mechanism by which T cells are protected from Fas/TNFR-induced cell death during T-cell activation. The applicant therefore proposes to further characterize IEX-1L expression in various in vitro models of T- cell activation to see whether a decrease in its expression is correlated to an increase in the sensitivity of T cells to Fas/TNFR- induced cell death. The applicant will also generate transgenic mice that express human IEX-1L in peripheral T cells under the control of H-2Kb promoter and dissect the protective role of IEX-1L in vivo. Transcription of the IEX-1L gene is controlled by mutiple transcription factors, which may be the key to regulate the sensitivity of T cells to apoptosis during various phases of the immune response. The applicant will determine these potential transcription factors in order to elucidate how differential expression of IEX-1L in T cells is achieved during immune response. Finally, they will identify the downstream targets that play an important role in the IEX-1L-mediated protection. These studies will help to elucidate the molecular basis of T-cell homeostasis and could potentially unravel novel targets for therapeutic intervention in lymphoproliferative disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
1R21AI045003-01
Application #
2833393
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Finerty, John F
Project Start
1999-03-01
Project End
2000-01-10
Budget Start
1999-03-01
Budget End
2000-01-10
Support Year
1
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