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Jyoti Misra Sen, M.Sc., Ph.D., Investigator Head, Lymphocyte Development Unit Laboratory of Immunology E-mail: jyoti-sen@nih.gov |
Biography: Dr. Sen received 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. She completed her post-doctoral training and then assumed a faculty position at the Harvard Medical School and Dana Farber Cancer Institute. While at Dana Farber Cancer Institute, she was named the David Abraham Fellow and Claudia Adams Barr Investigator. Her work was funded by grants from The Arthritis Foundation and NCI-NIH. She moved to the NIA in fall 2003. |
Overview: Stage-specific signal transduction and gene expression, resulting from reciprocal cell-cell interactions and locally produced cytokines and hormones, is critical for T cell development in the thymus. Cues from stromal cells regulate an exquisite balance of proliferation, quiescence, cell-death and cell-fate decisions in developing thymocytes. In turn, thymocytes regulate the maturation of thymic epithelial cells. Mature T cells migrate from the thymus to peripheral lymphoid organs where they differentiate into functional effector cells and mount immune response to pathogens. Finally, as the organism ages, the immune system deteriorates and the ability to combat pathogens declines. Research in the Misra Sen laboratory is focused on understanding signaling events in T cell development, function and aging. |
Current efforts are aimed at delineating the role of gene transcription by beta-catenin-TCF transcription factors. To this end we have manipulated the expression and function of beta-catenin and TCF genes. Several lines of investigation are currently ongoing. |
First, we are interested in the molecular mechanisms that regulate early stages of T-lymphocyte differentiation and transformation. Specifically, we study the role of the pre-T cell receptor (pre-TCR) in the regulation of early T cell homeostasis, survival, proliferation and differentiation. We have recently discovered that beta-catenin is a target of pre-TCR signaling; it is induced transiently by the pre-TCR and is down-regulated as the cells navigate the beta-selection checkpoint. Lack of beta-catenin expression impairs beta-selection whereas inability to down-regulate beta-catenin expression after beta-selection results in DNA damage, cellular senescence and p53-dependent apoptosis. In the absence of p53 function beta-catenin expression leads to an aggressive thymic lymphoma. Our future studies aim at the molecular understanding of the co-operation between pre-TCR and beta-catenin signals in normal T cell development and transformation. |
Second, we are interested in the molecular mechanisms that regulate lineage commitment and positive selection of alpha-beta-TCR expressing thymocytes. This step of thymocyte development ensures the generation of self-restricted but not self-reactive T cells and prevents autoimmunity while enabling immune response to pathogens. We have recently demonstrated that expression of beta-catenin regulates the timing of positive selection of CD8 T cells and enhances IL-7R signals in thymocytes during positive selection. Future studies aim to understand the molecular connections between signals from the TCR and beta-catenin during positive selection. |
Third, we are interested in the molecular mechanisms that regulate activation and function of mature T cells. We have demonstrated that beta-catenin and TCF cooperate to provide survival signals to activated CD4 and CD8 T cells. Future efforts are aimed at delineating how gene expression regulated by TCF and beta-catenin regulate CD4 T helper cell differentiation and CD8 T cell function. |
Fourth, we are interested in the molecular mechanisms involved in age-dependent thymic involution and aging. We have demonstrated that expression of beta-catenin in thymocytes results in accelerated age-dependent thymic involution. Future efforts aim to understand the molecular and cellular basis for accelerated thymic involution and in relating the findings to thymic involution in wild type mice. |
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