This Project will contribute to the overall goals of the Program by investigating the arm of TCR signaling thatactivates NF-KB, a transcription factor that is required for antigen-induced T cell proliferation and activation.The study of TCR signaling to NF-KB offers several opportunities to expand our understanding of how a Tcell interprets antigenic inputs. First, the mechanistic understanding of how the TCR activates NF-KB is farfrom complete. Critical components of this pathway remain undiscovered and it is likely that new players inthis pathway will also play important roles in other arms of TCR signaling studied in the Program.
In AIM 1, we will use a novel expression cloning strategy to identify enhancers and suppressors of TCR signaling toNF-KB. Second, maximal TCR-mediated NF-KB activation requires both TCR engagement by MHC plusantigen (signal 1) and costimulatory signals (signal 2).
In AIM 2, we will test the hypothesis that the CARD11-GADS interaction is required for CD28-mediated costimulatory signaling to NF-KB. Third, while it is clear thatmolecules that signal from the TCR to NF-KB are recruited to the immunological synapse (IS) in a dynamic,regulated manner, it is unclear how and why this is precisely accomplished.
In AIM 3, we will investigate howNF-KB signaling intermediates are recruited to the immunological synapse. This project will benefit fromsynergy with other projects in the Program.
AIM 1 will use Core C and should yield novel components ormodulators of TCR signaling pathways that can be studied in Projects 1, 2, 3, and 4 for roles in TCRclustering, Immunological Synapse (IS) formation and regulation, Sprouty!-mediated regulation, and calciumsignaling, respectively.
AIM 2 may offer molecular insight into how a T cell makes the cellular choice ofactivation or anergy, and will apply a mouse model and the expertise of J. Powell (Project 3).
AIM 3 will useCore B and technology developed by A. Kupfer (Project 2) and will contribute to the understanding of ISformation and structure during T cell activation. Our results should add to the understanding of how themolecular machinery of immune cells can recognize and interpret environmental cues, including pathogenicand nonpathogenic stimuli, and respond appropriately. Since the inappropriate response to stimuli can resultin ineffective immune surveillance, autoimmunity, or cancer, our results may yield molecular targets for newtherapies designed to treat diseases of the immune system.
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