PROJECT SUMMARY / ABSTRACT (OVERALL) Autoimmune endocrinopathies include a number of conditions in which the immune system destroys healthy hormone-producing tissues. These conditions affect a large number of Americans, many of them female, but have not yet been the focus of ACE studies in the past. Moreover, unlike most other autoimmune conditions, autoimmune endocrinopathies are not usually treated with immunotherapies, despite clear evidence that their etiology is immune-mediated. Thus, there is an urgent need to better understand autoimmune pathogenesis to identify targets for immunotherapies in these conditions. This new ACE proposal seeks to delineate mechanisms of autoimmune chronicity as critical pathways in the establishment of autoimmune endocrinopathies. The Principal Project delineates the epigenetic and transcriptional mechanisms underlying chronicity in autoimmune endocrinopathies. These studies will determine whether an epigenetic regulator UTX may a role in conversion of stem-like progenitor CD8+ T cells to effectors in autoimmune endocrinopathies. The Collaborative Project addresses spatial and temporal determinants of immune chronicity in cancer immunotherapy-related immune related adverse events (IRAEs). Endocrine IRAEs of great interest given the large proportion of cancer patients who now receive immunotherapies and develop these unwanted side effects. Finally, many autoimmune endocrinopathies are sex-biased, and the Pilot Project addresses sexual dimorphism in immune chronicity pathways. In particular, UTX is an X-linked gene that is differentially expressed in male vs. female CD8+ T cells, and we will explore UTX’s role in mediating sex differences in progenitor to effector conversion. Our ACE includes an Administrative Core, which will ensure efficient day-to-day operational support; an ACE Funds Management Core, which will administer financial and consortium agreements; and an ACE Biorepository Core, which takes advantage of the well-developed biorepository infrastructure system in place at UCLA. Our program will build a cohesive and multi-disciplinary team of immunologists, clinicians, and computational biologists to contribute our deep expertise to the ACE collaborative enterprise.