PROJECT SUMMARY/ABSTRACT To mount effective responses to specific pathogens, CD4+ T helper cells differentiate into specialized subsets that can recognize and promote clearance of foreign pathogens. However, dysregulation of these CD4+ T helper cells can lead to allergic and autoimmune conditions. One such subset is CD4+ T helper 2 (TH2) cells, which normally target parasites but are often implicated in asthma, a hyperinflammatory airway disease. Therefore, understanding the molecular mechanisms of TH2 cell regulation is a top priority for improving outcomes for asthma and other hyperinflammatory conditions. To this end, we have identified the Ikaros Zinc Finger (IkZF) transcription factor Eos as a candidate regulator of TH2 differentiation and function. Published work has largely associated Eos with immunosuppressive regulatory T cells. However, our data demonstrate a novel mechanism by which Eos propagates IL-2/STAT5 signaling within proinflammatory TH2 cells. Preliminary work from our lab shows Eos-deficient TH2 cells generated in vitro or in an in vivo allergic asthma model have reduced gene and/or protein expression of critical TH2 differentiation transcription factors (e.g. Gata3, Blimp-1), receptors (e.g. IL-2R⍺, IL-4R⍺) and effector cytokines (e.g. IL-4, IL-13). Excitingly, in vitro and overexpression studies also reveal Eos forms a novel complex with and promotes the tyrosine-phosphorylated activation of STAT5, suggesting a new mechanism whereby Eos governs CD4+ T cell differentiation. Through the work in this proposal, we will determine the T cell-intrinsic impacts of Eos on TH2 differentiation and define the molecular mechanisms by which Eos regulates STAT5 phosphorylation and target gene binding to drive the TH2 gene program. The proposed studies will be completed by the applicant, Jasmine Tuazon, an MD/PhD candidate in the laboratory of the Sponsor, Dr. Ken Oestreich. Dr. Oestreich is an Associate Professor in the Department of Microbial Infection and Immunity (MI&I) at The Ohio State University College of Medicine, which provides an outstanding technical and intellectual immunology research environment. Additionally, Ms. Tuazon will be mentored by a committee of immunology experts and collaborators, including Drs. Eugene Oltz (Chair, MI&I), Kymberly Gowdy (Assoc. Prof., Division of Pulmonary, Critical Care, and Sleep Medicine), and Jerry Lio (Asst. Prof., MI&I), who all provide strong, complementary expertise to Dr. Oestreich. Training will involve the development of conceptual and technical expertise, including pulmonary murine models, cellular and molecular immunology techniques, and integrated -omics approaches. Through this fellowship, Ms. Tuazon will also receive excellent professional development training in scientific communication, writing, and networking. Taken together, the proposed work will 1) provide novel mechanistic insight into the role of Eos in promoting TH2 differentiation and function via IL-2/STAT5 and 2) adv...