Islet-intrinsic sex differences in inflammatory signaling contribute to autoimmune diabetes susceptibility

Whereas most autoimmune diseases exhibit female predominance, type 1 diabetes (T1D) occurs more frequently in males after puberty, suggesting a role for sex hormones in disease modification. Because islet {beta} cells actively shape local immune responses, we hypothesized that sex-specific islet responses to inflammation contribute to this disparity. Using transcriptomic and proteomic analyses of human islets from male and female donors, we found that male islets exhibit a more aggressive response to proinflammatory cytokines, characterized by greater induction of interferon signaling and suppression of developmental signaling compared to female islets. Treatment of human islets and mouse {beta} cells with the sex hormone 17{beta}-estradiol (E2) suppressed inflammatory signaling and markers of {beta}-cell maturity while enhancing developmental gene programs. Complementary studies in non-obese diabetic (NOD) mice showed that E2 treatment reduces diabetes incidence and limits progression to severe insulitis. Islet single-cell RNA sequencing revealed that E2 treatment of NOD mice suppresses interferon signaling, chemokine production, and antigen presentation in {beta} cells, while reducing activation and cytotoxicity pathways in immune cells. In co-culture studies in vitro, E2 pretreatment of mouse islets reduces subsequent activation of T cells, and in an aggressive adoptive transfer model in vivo, E2 pretreatment of the recipient mice was found to attenuate hyperglycemia. These findings support a model in which E2-mediated {beta}-cell reprogramming reduces {beta}-cell immunogenicity and promotes local immune tolerance, offering mechanistic insight into sex-biased T1D susceptibility.