Engagement of the T cell receptor (TCR) triggers a number of intracellular signaling events that lead to the differentiation and activation of T cells. Several studies have shown that SLP-76 plays a central role in T cell activation and T cell development, as mice deficient in SLP-76 lack mature T cells. SLP-76 has three functional domains: an acidic domain with three phosphorylatable tyrosines, a central proline-rich domain, and a C-terminal SH2 domain. Of these domains, mutation of the three N-terminal tyrosines results in the most profound defects in T cell development and function. It is hypothesized that the individual tyrosines of SLP-76 activate specific signaling cascades required for T cell development including thymocyte selection, and T cell differentiation and function. This hypothesis will be tested by 1) analyzing SLP-76 deficient Jurkat cells reconstituted with SLP-76 bearing mutations at one or multiple tyrosine phosphorylation sites, 2) analyzing SLP-76 knock-in mice expressing tyrosine mutations at particular tyrosine residues and 3) mating SLP-76 knock-in mice to T cell receptor transgenic mice to evaluate thymocyte selection and mechanisms of T cell tolerance. Understanding how T cells transmit signals to direct thymocyte development and mature T cell function is critical to understanding the mechanisms to drive several disease processes including autoimmune diseases such as arthritis. This work will be performed by Dr. Martha S. Jordan at the Abramson Institute at the University of Pennsylvania. Dr. Jordan's background in cellular immunology and current training in molecular immunology provides her with a distinct angle from which to approach questions of T cell development. This proposal will provide her with the tools and reagents required to study T cell function in vitro and in vivo, in normal and diseased states as an independent investigator at a research university. Full access to faculty and services provided by the University of Pennsylvania, especially those within the Abramson Institute, will ensure the success of this proposal. ? ? ?

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Scientist Development Award - Research & Training (K01)
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Arthritis and Musculoskeletal and Skin Diseases Special Grants Review Committee (AMS)
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Mancini, Marie
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University of Pennsylvania
Internal Medicine/Medicine
Schools of Medicine
United States
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Carty, Shannon A; Koretzky, Gary A; Jordan, Martha S (2014) Interleukin-4 regulates eomesodermin in CD8+ T cell development and differentiation. PLoS One 9:e106659
Kim, Jiyeon S; Sklarz, Tammarah; Banks, Lauren B et al. (2013) Natural and inducible TH17 cells are regulated differently by Akt and mTOR pathways. Nat Immunol 14:611-8
Kim, Jiyeon S; Jordan, Martha S (2013) Diversity of IL-17-producing T lymphocytes. Cell Mol Life Sci 70:2271-90
Chang, John T; Ciocca, Maria L; Kinjyo, Ichiko et al. (2011) Asymmetric proteasome segregation as a mechanism for unequal partitioning of the transcription factor T-bet during T lymphocyte division. Immunity 34:492-504
Kim, Jiyeon S; Smith-Garvin, Jennifer E; Koretzky, Gary A et al. (2011) The requirements for natural Th17 cell development are distinct from those of conventional Th17 cells. J Exp Med 208:2201-7
Gordon, Scott M; Carty, Shannon A; Kim, Jiyeon S et al. (2011) Requirements for eomesodermin and promyelocytic leukemia zinc finger in the development of innate-like CD8+ T cells. J Immunol 186:4573-8
Wu, Gregory F; Corbo, Evann; Schmidt, Michelle et al. (2011) Conditional deletion of SLP-76 in mature T cells abrogates peripheral immune responses. Eur J Immunol 41:2064-73
Smith-Garvin, Jennifer E; Burns, Jeremy C; Gohil, Mercy et al. (2010) T-cell receptor signals direct the composition and function of the memory CD8+ T-cell pool. Blood 116:5548-59