PROJECT SUMMARY / ABSTRACT (PILOT PROJECT) A number of autoimmune endocrinopathies are sex biased, with strong female predisposition For instance, female:male prevalence ratios have been estimated to be 19:1 for autoimmune thyroiditis. Previous work has suggested a role for divergent levels of sex hormones as an underlying cause. In particular, increased androgen signaling drives expression of the transcription factor TCF7, which dampens conversion of CD8+ T cell progenitor to effector cells. The resultant decrease in the pool of effectors, the cell type mediating direct destruction of endocrine tissues, protects from endocrine autoimmunity. Our recent data point to an additional role for increased X chromosome copy number in female sex bias, since deficiency of the X-linked gene UTX also suppresses progenitor to effector conversion. Thus, we will test the hypothesis that sex differences in human autoimmune endocrinopathies is driven by both increased X-linked UTX expression and lower androgen levels in females. In Aim 1, we will determine the role of the X-linked genes promoting progenitor to effector conversion. We will utilize virally-mediated UTX overexpression to determine the effects of this X-linked gene in effector differentiation. Additionally, we will query effector differentiation in CD8+ T cells from patients with Klinefelter Syndrome, a condition in which phenotypic males have an extra X chromosome (47XXY). In Aim 2, we will determine the effects of androgen and estrogen signaling on TCF7 expression and progenitor to effector conversion. Understanding mechanisms underlying sex differences is critical for identifying new drug targets and tailoring therapeutic approaches in a personalized manner for patients with autoimmune endocrinopathies.