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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
1F32CA103374-01
Application #
6692085
Study Section
Special Emphasis Panel (ZRG1-F07 (20))
Program Officer
Lohrey, Nancy
Project Start
2004-01-01
Project End
2006-12-31
Budget Start
2004-01-01
Budget End
2004-12-31
Support Year
1
Fiscal Year
2003
Total Cost
$36,754
Indirect Cost
Name
University Hospital Basel
Department
Type
DUNS #
483322702
City
Basel
State
Country
Switzerland
Zip Code
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Gil, Diana; Schrum, Adam G; Alarcon, Balbino et al. (2005) T cell receptor engagement by peptide-MHC ligands induces a conformational change in the CD3 complex of thymocytes. J Exp Med 201:517-22
Schrum, Adam G; Palmer, Ed; Turka, Laurence A (2005) Distinct temporal programming of naive CD4+ T cells for cell division versus TCR-dependent death susceptibility by antigen-presenting macrophages. Eur J Immunol 35:449-59
Teixeiro, Emma; Daniels, Mark A; Hausmann, Barbara et al. (2004) T cell division and death are segregated by mutation of TCRbeta chain constant domains. Immunity 21:515-26
Treves, Susan; Franzini-Armstrong, Clara; Moccagatta, Luca et al. (2004) Junctate is a key element in calcium entry induced by activation of InsP3 receptors and/or calcium store depletion. J Cell Biol 166:537-48