This Project will contribute to the overall goals of the Program by investigating the arm of TCR signaling that activates 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 T cell interprets antigenic inputs. First, the mechanistic understanding of how the TCR activates NF-KB is far from complete. Critical components of this pathway remain undiscovered and it is likely that new players in this 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 to NF-KB. Second, maximal TCR-mediated NF-KB activation requires both TCR engagement by MHC plus antigen (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 that molecules 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 how NF-KB signaling intermediates are recruited to the immunological synapse. This project will benefit from synergy with other projects in the Program.
AIM 1 will use Core C and should yield novel components or modulators of TCR signaling pathways that can be studied in Projects 1, 2, 3, and 4 for roles in TCR clustering, Immunological Synapse (IS) formation and regulation, Sprouty!-mediated regulation, and calcium signaling, respectively.
AIM 2 may offer molecular insight into how a T cell makes the cellular choice of activation or anergy, and will apply a mouse model and the expertise of J. Powell (Project 3).
AIM 3 will use Core B and technology developed by A. Kupfer (Project 2) and will contribute to the understanding of IS formation and structure during T cell activation. Our results should add to the understanding of how the molecular machinery of immune cells can recognize and interpret environmental cues, including pathogenic and nonpathogenic stimuli, and respond appropriately. Since the inappropriate response to stimuli can result in ineffective immune surveillance, autoimmunity, or cancer, our results may yield molecular targets for new therapies designed to treat diseases of the immune system.
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| Hickey, John W; Isser, Ariel Y; Vicente, Fernando P et al. (2018) Efficient magnetic enrichment of antigen-specific T cells by engineering particle properties. Biomaterials 187:105-116 |
| Bettencourt, Ian A; Powell, Jonathan D (2017) Targeting Metabolism as a Novel Therapeutic Approach to Autoimmunity, Inflammation, and Transplantation. J Immunol 198:999-1005 |
| Kosmides, A K; Meyer, R A; Hickey, J W et al. (2017) Biomimetic biodegradable artificial antigen presenting cells synergize with PD-1 blockade to treat melanoma. Biomaterials 118:16-26 |
| Tiper, Irina V; Temkin, Sarah M; Spiegel, Sarah et al. (2016) VEGF Potentiates GD3-Mediated Immunosuppression by Human Ovarian Cancer Cells. Clin Cancer Res 22:4249-58 |
| Pollizzi, Kristen N; Sun, Im-Hong; Patel, Chirag H et al. (2016) Asymmetric inheritance of mTORC1 kinase activity during division dictates CD8(+) T cell differentiation. Nat Immunol 17:704-11 |
| Schütz, Christian; Varela, Juan Carlos; Perica, Karlo et al. (2016) Antigen-specific T cell Redirectors: a nanoparticle based approach for redirecting T cells. Oncotarget 7:68503-68512 |
| Pollizzi, Kristen N; Patel, Chirag H; Sun, Im-Hong et al. (2015) mTORC1 and mTORC2 selectively regulate CD8? T cell differentiation. J Clin Invest 125:2090-108 |
| Perica, Karlo; Kosmides, Alyssa K; Schneck, Jonathan P (2015) Linking form to function: Biophysical aspects of artificial antigen presenting cell design. Biochim Biophys Acta 1853:781-90 |
| Bruns, Heiko; Bessell, Catherine; Varela, Juan Carlos et al. (2015) CD47 Enhances In Vivo Functionality of Artificial Antigen-Presenting Cells. Clin Cancer Res 21:2075-83 |
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