Roles for Ets1 in thymic selection and CD8αα IEL development

PROJECT SUMMARY Thymic selection is crucial for generating functional and self-tolerant T cells, yet the mechanisms underlying the development of unconventional T cell lineages, such as CD8αα intraepithelial lymphocytes (IELs), remain poorly understood. CD8αα IELs possess innate-like features and play essential roles in maintaining intestinal integrity. Dysregulation of CD8αα IELs can contribute to intestinal pathologies like celiac disease. This study focuses on investigating the role of the transcription factor Ets1 in thymic selection and its impact on IEL development and function. Ets1 is a signal-regulated transcription factor that is implicated in the pathogenesis of multiple autoimmune disorders. Despite its known roles in early T cell development and peripheral T cell function, Ets1’s specific role in thymic selection remains poorly understood. Furthermore, Ets1 is implicated in regulating responses to IL-15 and TGF-β, crucial for CD8αα IEL maturation and function, highlighting its significance in intestinal homeostasis. Preliminary data using Ets1-deficient mice indicate that Ets1 restricts the development of IEL precursors (IELps) in the thymus and prevents premature egress of immature thymocytes. Moreover, Ets1 may promote clonal deletion of autoreactive T cells. This study aims to elucidate the molecular mechanisms underlying these observations. Aim 1 aims to determine how Ets1 regulates thymic selection by investigating its impact on positive selection and clonal deletion. TCR-transgenic models, flow cytometry, and CUT&RUN will be used to determine how Ets1 regulates thymic selection. Aim 2 focuses on assessing the functional consequences of Ets1 deficiency in CD8αα IELs. By examining IELp maturation and peripheral function, this aim aims to elucidate how Ets1 influences the development and function of these cells. Overall, this study aims to provide novel insights into the regulatory mechanisms governing thymic selection and the role of Ets1 in shaping T cell development and peripheral immune homeostasis, with potential implications for understanding autoimmune diseases.