T helper cells differentiate into different subsets, which are responsible for controlling the outcome of an immune response. For example, Th1 cells direct the immune response against viruses and intracellular bacteria, while Th17 cells are required to eradicate certain extracellular bacteria. However, dysregulated T helper responses can cause immune pathology such as inflammatory bowel disease or multiple sclerosis. The transcription factor Ets-1 plays a major role in promoting IL-2 and IFN-? production and Th1 differentiation. At the same time, Ets-1 inhibits Th17 differentiation mainly through promoting IL-2. In addition to affecting T helper cell differentiation, IL-2 plays a pivotal role in immune regulation. While it is required for the induction of T cell memory, IL-2 also maintains regulatory T cells and therefore peripheral tolerance.
The first aim of this proposal is directed at elucidating the molecular mechanisms by which Ets-1 regulates IL-2 production. Secondly, Ets-1 is expressed both in Th1 and Th17 cells, although it inhibits differentiation of the latter. It is unknown how Ets-1 activity is regulated in T cells. Activating and inactivating phosphorylation events that have been proposed in other cell types only play a very modest role in T cells. Therefore, other regulatory mechanisms must exist. Dr. Grenningloh has recently identified a mutant of Ets-1 that fails to promote IL-2 or IFN-? production. The second part of this proposal aims at identifying the defect of this mutant on a molecular level. This should shed light on the regulation of Ets-1 activity in T cells as opposed to other cell types.
T helper cells direct the immune response against infectious agents but can also cause autoimmune disease. The goal of this study is to understand the function of a transcription factor, Ets-1, that regulates T helper cell function and might therefore be a useful target for the development of new treatments.
| Tsao, Hsiao-Wei; Tai, Tzong-Shyuan; Tseng, William et al. (2013) Ets-1 facilitates nuclear entry of NFAT proteins and their recruitment to the IL-2 promoter. Proc Natl Acad Sci U S A 110:15776-81 |
| Lee, Choong-Gu; Kwon, Ho-Keun; Sahoo, Anupama et al. (2012) Interaction of Ets-1 with HDAC1 represses IL-10 expression in Th1 cells. J Immunol 188:2244-53 |
| Grenningloh, Roland; Tai, Tzong-Shyuan; Frahm, Nicole et al. (2011) Ets-1 maintains IL-7 receptor expression in peripheral T cells. J Immunol 186:969-76 |
| Zamisch, Monica; Tian, Linhua; Grenningloh, Roland et al. (2009) The transcription factor Ets1 is important for CD4 repression and Runx3 up-regulation during CD8 T cell differentiation in the thymus. J Exp Med 206:2685-99 |
