In an effort to identify factors responsible for the maintenance of the anergic phenotype we employed a novel statistical algorithm, HAM (Hypothesis based Analysis of Microarrays) to interrogate a data base consisting of T cell stimulated under conditions that either promote full T cell activation or anergy. Among the genes identified by this approach was Sprouty 1 a member of an evolutionarily conserved family of inducible inhibitors that has been mostly studied in the field of Development. In particular Sprouty 1 has been implicated in negative feedback loops that impart spatial temporal constraints to intracellular signals. In this project we will dissect the mechanism by which Sprouty 1 inhibits T cell activation and maintains the anergic state.
In Aim I we will determine the mechanisms governing the expression of Sprouty 1 and the precise biochemical mechanisms by which Sprouty 1 inhibits TCR-induced signaling.
In Aim II, in collaboration with Project 2, we will determine how the structure and intracellular trafficking of Sprouty 1 dictates its inhibitory function.
In Aim III using conditional Sprouty 1 null mice we will determine the role of Sprouty 1 in regulating viral, """"""""self and tumor immune responses in vivo. Overall dissecting the mechanisms by which Sprouty 1 inhibits T cell function should provide important insight in terms of identifying novel pharmacologic targets. For example in autoimmune diseases and transplantation, the goal would be to inhibit T cell activation but leave Sprouty 1 signaling intact. Alternatively, for tumor immunity, developing strategies to inhibit Sprouty 1 function and thus enhance the anti-tumor response.
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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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