T lymphocytes not only play a central role in adaptive immunity but also are pathogenic in many autoimmune and allergic diseases. Thus far, several functional subsets of peripheral T cells have been identified. Despite the differences in function, all subsets are derived from common lymphoid precursors. The differentiation of common lymphoid precursors into various functionally distinct T cells is controlled by several T cell-specific and non-specific genes, including transcription factors, cytokines, and signaling molecules. Research in my laboratory is directed toward understanding the transcriptional regulation of T cell development and function. We are particularly interested in studying the roles of several transcription factors that are preferentially expressed in T cells. Two of the factors that are being thoroughly investigated are GATA-3 and Ets-1.
GATA-3 is a T cell-specific transcription factor. Previous studies have indicated that GATA-3 is essential for the development of the T cell lineage and might function as a master switch for the differentiation of type 2 helper T (Th2) cells. By studying conditional GATA-3-deficient mice, we have discovered that GATA-3 is required in several steps of T cell development. Most strikingly, GATA-3 is absolutely essential for the generation of CD4+Th cells but not CD8+Tc cells. In addition, Th2 immune responses are markedly impaired in the absence of GATA-3. The mechanism of action of GATA-3 and its emerging role in other functional lineages of T cells are currently under investigation. We have also discovered that Ets-1, the prototype of ETS family of transcription factors, reciprocally regulates the function of Th1 and Th17 cells and that Ets-1-deficient Th cells fails to induce colitis in lymphopenic mice, an animal model of human inflammatory bowel diseases. We are investigating how Ets-1 controls the Th1/Th17 balance and the colitogenicity of Th cells.
Through the studies of GATA-3, Ets-1, and other lineage-specific genes, we wish to gain insight into the development, activation, and differentiation of T cells and to discover novel approaches to manipulate adaptive immune responses and to treat T cell-mediated autoimmune diseases.
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Papers & Publications:
Moisan, J., R. Grenningloh, E. Bettelli, M. Oukka, and I. C. Ho. 2007. Ets-1 is a negative regulator of Th17 differentiation. J Exp Med 204:2825.
Pai, S. Y., B. Y. Kang, A. Sabadini, E. Parisini, M. L. Truitt, and I. C. Ho. 2008. Distinct structural requirements of GATA-3 in the regulation of thymocyte and Th2 cell differentiation. J Immunol 180:1050.
Grenningloh, R., S. C. Miaw, J. Moisan, B. J. Graves, and I. C. Ho. 2008. Role of Ets-1 phosphorylation in the effector function of Th cells. Eur J Immunol 38:1700.
Dardalhon, V., A. Awasthi, H. Kwon, G. Galileos, W. Gao, R. A. Sobel, M. Mitsdoerffer, T. B. Strom, W. Elyaman, I. C. Ho, S. Khoury, J. van Snick, M. Oukka, and V. K. Kuchroo. 2008. IL-4 inhibits TGF-b-induced-Foxp3+T cells and generates a Foxp3- IL-9/IL-10-producing helper/effector T cell population. Nat Immunol 9:1347.
Ho, I. C., T. S. Tai, and S. Y. Pai. 2009. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat Rev Immunol (in press).
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