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Lee, Youjin

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Lee, Youjin

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2013 - 20152

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Author's Publications: search.filters.isAuthorOfPublication.319f491e-c280-4cc8-9cb4-53e9daba0ae7

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    Dynamic regulatory network controlling Th17 cell differentiation
    (2013) Yosef, Nir; Shalek, Alex K.; Gaublomme, Jellert; Jin, Hulin; Lee, Youjin; Awasthi, Amit; Wu, Chuan; Karwacz, Katarzyna; Xiao, Sheng; Jorgolli, Marsela; Gennert, David; Satija, Rahul; Shakya, Arvind; Lu, Diana Y.; Trombetta, John J.; Pillai, Meenu R.; Ratcliffe, Peter J.; Coleman, Mathew L.; Bix, Mark; Tantin, Dean; Park, Hongkun; Kuchroo, Vijay; Regev, Aviv
    Despite their importance, the molecular circuits that control the differentiation of naïve T cells remain largely unknown. Recent studies that reconstructed regulatory networks in mammalian cells have focused on short-term responses and relied on perturbation-based approaches that cannot be readily applied to primary T cells. Here, we combine transcriptional profiling at high temporal resolution, novel computational algorithms, and innovative nanowire-based tools for performing perturbations in primary T cells to systematically derive and experimentally validate a model of the dynamic regulatory network that controls Th17 differentiation. The network consists of two self-reinforcing, but mutually antagonistic, modules, with 12 novel regulators, whose coupled action may be essential for maintaining the balance between Th17 and other CD4+ T cell subsets. Overall, our study identifies and validates 39 regulatory factors, embeds them within a comprehensive temporal network and reveals its organizational principles, and highlights novel drug targets for controlling Th17 differentiation.
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    Pathogenic Potential ofCD4 T Cells in Autoimmune Diseases
    (2015-05-22) Lee, Youjin; Sharpe, Arlene; Kuchroo, Vijay; Tsokos, George; Carroll, Michael
    The molecular mechanisms governing T helper (Th) cell differentiation and function have revealed a complex network of transcriptional and protein regulators. Cytokines not only initiate the differentiation of CD4 T helper into subsets, but also influence the identity, plasticity and effector function of a T cell. Th17 cells, named for producing interleukin 17 (IL-17) as their signature cytokine, secrete a cohort of other cytokines including IL-22, IL-21, IL-10, IL-9, IFNγ, and GM-CSF. In recent years, Th17 cells have emerged as a key player in host defense against both extracellular pathogens and fungal infections. Th17 cells have also been implicated as one of the main drivers in the pathogenesis of autoimmune diseases such as multiple sclerosis, which are likely mediated in part by the cytokines that Th17 cells produce. Here in this thesis, we explore the pathogenic regulation of CD4 T cells in the context of the autoimmune diseases, multiple sclerosis and inflammatory bowel disease. We attempt to understand the mechanisms by which Th17 cells promote pathogenic inflammation by utilizing high throughput whole genome mRNA sequencing as well as next generation single cell RNA sequencing to uncover novel regulators that drive effector function. Advances in high throughput genomic sequencing allowed us to uncover an unexpected heterogeneity and diversity in Th17 cell populations. The four studies outlined in this thesis reconcile many confounding questions in the areas of autoimmune pathogenicity and reveal key regulators that define the various functional states of Th17 cells.