Jyoti M. Sen, M.Sc., Ph.D.
M. Sc. – Indian Institute of Technology (IIT), Kanpur, India
Ph. D. – Columbia University, New York City
Adjunct Faculty, School of Medicine Immunology Graduate Program
Johns Hopkins University
Senior Investigator, National Institute on Aging/NIH
Chief, Immune Cells & Inflammation Section
National Institute on Aging, NIH
251 Bayview Blvd., Rm. 08C218
Baltimore, MD 21224
Keywords: T cell development and function; immune aging; systemic inflammation; signal transduction; gene expression.
We are studying molecular mechanisms that regulate development and function of immune cells and control age-associated systemic inflammation. The renewal of mammalian immune system from bone marrow derived hematopoietic stem cells is orchestrated throughout life by events that are robust in young individuals but decline with age, resulting in poor outcomes of vaccinations and medical interventions as well as in chronic systemic inflammation in older people. To address these issues, we are studying the molecular basis for immune cell development, function and age-related decline in the immune system.
Our recent work has focused on the transcription factor T cell factor (TCF)-1, encoded by Tcf7 gene, and its co-factors beta-catenin and Groucho. We have demonstrated that in addition to the well-accepted role of TCF1 and beta-catenin downstream of the Wnt signaling pathway the T cell receptor (TCR) and pre-TCR signals regulate the function of these transcription factors in developing thymocytes and T cells. Our studies have delineated a critical role for TCF1 and beta-catenin in the development and selection of conventional T cells in the thymus. In addition to facilitating the development of conventional T cells the mammalian thymus is the site of generation of innate immune cells including the invariant natural killer T iNKT and innate memory-like iCD8 T cells. Development of these innate T cells is also critically regulated by TCF1 and beta-catenin dependent gene expression. Finally, TCF1 and beta-catenin regulate gene expression that facilitates thymic epithelial cell and thymocyte cross-talk and thereby control age-associated thymic involution. Thus, TCF1 and beta-catenin dependent gene expression is intricately linked to several aspects of thymic function.
Mature T cells mediate immune response to pathogens and neoplasms in all mammalian tissues. A major onus on the immune system is to provide measured and adequate protection from offending elements while repressing autoimmunity. Molecular mechanisms that control the tightly maintained balance between appropriate and autoimmune response of immune cells remain to be elucidated. Our studies show that TCF1 and beta-catenin control immune function by regulating antigen dependent T helper (Th) cell differentiation. TCF1 and beta-catenin promote differentiation of Th2 cells, involved in allergy and asthma. By contrast, TCF1-dependent transcriptional repression critically inhibits autoimmunity by suppressing Th1 and Th17 responses. We believe insights gained from our studies will aid our ability to design pharmacologic manipulation of TCF1 and beta-catenin expression and function to control the fine balance between immune and autoimmune response.
We anticipate that our work to understand the mechanisms by which the immune system protects against invading pathogens without triggering autoimmune responses will lead to insights that improve the quality of human life.
Yu, Q., Sharma, A., Oh, S. Y., Moon, H. G., Hossain, M. Z., Salay, T. M., Leeds, K. E., Du, H., Wu, B., Waterman, M. L., Zhu, Z., Sen. J. M. T cell factor 1 initiates the T helper type 2 fate by inducing the transcription factor GATA-3 and repressing interferon-gamma. Nature Immunology. 9: 992-9, 2009.
Yu Q, Sharma A, Sen J. M. TCF1 and beta-catenin regulate T cell development and function. Immunological Research. 47: 45-55, 2010.
Yu, Q., Sharma, A., Ghosh, A. and Sen, J. M. T Cell Factor-1 negatively regulates expression of IL-17 family of cytokines and protects mice from experimental autoimmune encephalomyelitis. Journal of Immunology. 186:3946-52. 2011. Comment. JI 186:3801.
Sharma, A., Chen, Q., Nguyen, T., Yu, Q. and Sen, J. M. T cell factor-1 and ?eta-catenin control the development of memory-like CD8 thymocytes. 2011. Journal of Immunology. 188:3859-68, 2012 issue. Comment. JI 188:3557.
Sharma A. and Sen, J. M. Molecular basis for the tissue specificity of ?eta-catenin oncogenesis. 2011. Oncogene 32:1901-1909, 2013.