PROJECT SUMMARY The broad goal of this proposal is to define a five-year scientific training and career development plan to prepare the candidate to become an independent physician-scientist in the domain of primary immune regulatory disorders (PIRD). The field of primary immune deficiency is rapidly growing, now recognizing around 500 monogenic inborn errors of immunity, of which at least 10% result in immune dysregulation. An increasing number of these disorders are caused by mutations in the JAK-STAT signaling pathway, a signaling cascade that is also a frequent therapeutic target in disorders of the immune system and malignancy. To deliver effective diagnostic, treatment, and management decisions, an in-depth understanding of cell-specific aberrations in these pathways is needed. STAT3 gain-of-function (GOF) syndrome is a PIRD with multi-organ involvement and early onset autoimmunity. We recently demonstrated T cell dysregulation with inherent Th1- skewing and an isolated defect in peripheral Treg cell generation in a model of STAT3 GOF syndrome— findings that challenge current hypotheses regarding disease pathogenesis. The primary scientific goal of this research project is to study the mechanisms contributing to T cell dysregulation in STAT3 GOF syndrome. To achieve this, we will study critical interactions between T and B cells as well as the development, polarization, and function of these cells. Immunophenotyping and transcriptional analysis will be done using a murine model of STAT3 GOF syndrome and viral infection models. In addition, we will establish the impact of STAT3 GOF on antigen-specific responses and mucosal tolerance using a TCR transgenic mouse system and a viral infection model. Furthermore, we plan to utilize a series of in vitro assays to define the impact of STAT3 GOF on T cell polarization in patients. The proposed career development plan incorporates training in technical expertise, grant and scientific writing, responsible conduct of research, as well as mentorship through individualized instruction, didactic courses, University-sponsored seminars, and presentation and attendance at national conferences. Washington University School of Medicine is the ideal training environment given its rich scientific and collaborative culture, and commitment to training physician-scientists. The training will occur under the guidance of the candidate's primary mentor, Dr. Megan Cooper, and the scientific advisory committee, along with a strong group of collaborators. The proposed career development plan and research aims outlined in this application will provide the candidate with the necessary skills and knowledge to become an independent physician-scientist and make significant contributions to the field of primary immune regulatory disorders. Results from these studies have the potential to uncover new biomarkers, targetable cellular pathways, and further insight into disease pathogenesis and human immunology.