Transcription Factor Ets-1 Negatively Regulates the Generation of Peripheral Treg Cells Jan. 16 (MON) 16:30 / Auditorium (1F), PBC Choong-Gu Lee Academy of Immunology and Microbiology (AIM), IBS E26 transformation-specific-1 (Ets-1), a member of the ETS family of transcription factors, controls a wide variety of cellular processes and plays an important role in autoimmune diseases. Previous studies in Ets-1 deficient (Ets-1-/-) mice have demonstrated the important functions of Ets-1 in development, proliferation, and survival of T cells. Regulatory T cells (Treg cells) constitute a population of CD4+ T cells that limits immune responses. Transcription factor Foxp3 plays key roles in determining the development and function of Treg cells. However, the molecular mechanisms that trigger or maintain its expression remain incompletely understood. Previous data demonstrate that Ets-1 is required for the development of natural Treg cells. Though Ets-1-/- mice developed T cell-mediated splenomegaly and lupus-like autoimmune phenotype, the mice showed no severe autoimmune disease symptoms in steady state even at old age. We unexpectedly found considerable amount of CD4+ Foxp3+ T cells in the peripheral lymphoid tissues of Ets-1-/- mice. Interestingly, most of them were CD25-Nrp1-, suggesting the possibility of peripherally induced Foxp3+ regulatory T (pTreg) cells. These CD25-Foxp3+ T cells express reduced levels of Treg phenotypic markers such as ICOS, GITR and CTLA4 and exhibit naïve-like T cell phenotypes (CD44lo CD62L+). These findings prompted us to hypothesize that these cells might be harbouring a state of intermediate gene expression that holds them at a transitioning stage between naïve T cells to pTreg transition. In concert to this hypothesis, naïve T cells from Ets-1-/- mice were more prone to become induced Treg (iTreg) cells in vitro and in vivo. Using knock-down and overexpression systems, we have confirmed again the negative role of Ets-1 in Foxp3 regulation through the ETS domain (known for DNA binding). In summary, our data suggests that Ets-1 may repress Foxp3 expression, thereby acting as an important negative regulator of peripherally induced regulatory T cells. Inquiry: Dr. You Jeong Lee (279-2359) or AIM Administrative Team (Tel.279-8628, E-mail: varsha@ibs.re.kr)