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Abstract
Type 1 diabetes (T1D) is a disease of insulin deficiency resulting from autoimmune destruction of the pancreatic β cells. Over a century after the discovery of insulin and its life-saving therapeutic utility, our understanding of who is at risk for T1D, what triggers disease onset, and how to prevent it remain limited. Increasing evidence implicates dysfunction of β cells themselves- including inflammatory signaling, endoplasmic reticulum stress, and neoantigen formation and presentation- in their targeting by autoreactive immune cells. In this dissertation, I make use of the observation that T1D occurs more frequently in males after puberty and interrogate the role of sex in shaping β cell response to inflammation, a potential trigger for T1D onset. I hypothesized that female β cells may be preconditioned to respond more adaptively to inflammatory challenges and thus may be protected from developing more immunogenic phenotypes. I first challenged human islets from both male and female donors with proinflammatory cytokines and compared their responses using bulk RNA sequencing and mass spectrometry-based proteomics. To determine whether sexual dimorphism in islet inflammatory response may be driven by exposure to sex hormones, I utilized in vitro and in vivo treatments with 17 β-estradiol to study its influence on the β cell’s transcriptome, proteome, and vulnerability to autoimmune diabetes. I provide evidence that human islets from male donors exhibit an exacerbated proinflammatory response to an identical inflammatory stimulus compared to islets from female donors, and I demonstrate that 17β-estradiol suppresses diabetogenic inflammatory signaling and antigen presentation at the β cell, protecting against autoimmune diabetes in the non-obese diabetic model of T1D. Overall, the data presented in this dissertation support the notion that sex differences in β cell response to inflammation could contribute to the male predominance of- and relative female protection from-T1D.