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Immune Cells and Inflamation Section Jyoti Misra Sen, M.Sc., Ph.D., Senior Investigator |
| Biography: Dr. Misra Sen earned her M.Sc. in Chemistry from Indian Institute of Technology at Kanpur and Ph. D. in Biological Sciences from Columbia University in New York City. After completing David Abraham Fellowship at Dana Farber Cancer Institute she was named Claudia Adams Barr Investigator with faculty appointments at Dana Farber Cancer Institute and Harvard Medical School. Her work was funded by grants from The Barr Foundation, The Arthritis Foundation and NCI-NIH. She moved to the NIA-NIH in 2003. |
Overview: Renewal of mammalian immune system from bone marrow derived hematopoietic stem cells throughout life is orchestrated by signaling events that remain poorly understood. This process is robust in young individuals but declines with age, which results in poor outcome of vaccinations and medical interventions as well as in chronic systemic inflammation in older people. We are interested in understanding mechanisms that mediate proper maintenance of immune cells throughout life and control systemic inflammation. The mammalian thymus provides a unique microenvironment that promotes the development of conventional T cells. The thymus is also the site where Natural Killer T (iNKT) cells and innate-like CD8 (iCD8) T cells develop. Mature cells egress the thymus to populate the peripheral lymphoid organs and mediate immune response. These events are outlined in the diagram. |
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Currently, research in my laboratory is focused on understanding the signals received by thymocytes that result in lineage choice at each stage of T cell development in the thymus. The early thymic precursors receive a Notch signal from the thymic environment, which leads to commitment to the T lineage. One major transcription factor that regulates subsequent events
in T cell development is T Cell Factor (TCF)-1. TCF1 represses gene expression in conjunction with co-factors such as Groucho (Grg) and
activates gene transcription in cooperation with ß-catenin. TCF1 and ß-catenin regulate T cell development at multiple stages (see diagram). Mature T cells migrate to peripheral lymphoid organs and further differentiate to provide effective immune protection. Mature T cells express
TCF1 and induce ß-catenin expression in a signal driven manner. During
T helper cell differentiation we have found that TCF1 critically regulates GATA3 expression and Th2 differentiation. During Th1 and Th17 differentiation TCF1 directly regulates IFNγ and IL-17 cytokine gene expression. Using TCF1-deficient mice in combination with IFNγ and
IL-17 reporter mice we plan to dissect the molecular mechanisms by
which TCF1 represses spurious cytokine gene expression by T cells
and protects mice from autoimmune diseases. |
Mechanisms that control age-associated thymic involution are not understood. In particular, crosstalk resulting from thymocyte and thymic epithelial cell (TEC) interactions, which critically regulates thymocyte development and thymic involution, remains elusive. A comprehensive effort to understand the molecular basis for thymocyte-TEC crosstalk is one focus of our experimental efforts. In this regard, we have shown that ß-catenin over-expression in thymocytes leads to premature thymic involution and age-dependent T cell aging. We have also demonstrated that enforced expression of ß-catenin in thymocytes results in cellular senescence, growth arrest and p53-dependent cell death. Current studies are directed at understanding if ß-catenin dependent mechanisms regulate age-dependent thymic involution in C57BL/6 mice. ß-Catenin dependent signaling has been shown to participate in tissue aging in conjunction with Klotho. Using Klotho-deficient and Klotho-transgenic mice in combination with ß-catenin overexpressing mice we will determine the molecular interactions between these signaling pathways in T cell aging and thymic involution. These studies will inform on the molecular basis for age-associated thymic involution, which might provide insights into the design of strategies that help combat age-dependent thymic involution and paucity of newly generated T cells in the elderly. |
In summary, the overall goal of our studies is to understand mechanisms by which the immune system provides protections from invading pathogens while restraining from autoimmune responses throughout life. |
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Immune Cells and Inflammation Section Left to Right: Qinghua Chen, Rosa Berga Bolanos, Archna Sharma and Dil Afroz Sultana |
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