The role of T cells in uterine turnover and homeostasis 2258113

Abstract Introduction The endometrium undergoes a coordinated and cyclic turnover that is unlike any other mammalian tissue. In mice, this process entails a 20-40% reduction in endometrial cellularity over a 12—24-hour time frame. This remarkable coordination raises fundamental questions about how such rapid and synchronized cell death is achieved across distinct cell types. Notably, the healthy, non-pregnant endometrium, in both mice and humans, harbors diverse immune cells that, in principle, could mediate or facilitate endometrial breakdown. T cells stand out as compelling candidates due to their ability to recognize and respond to tissue-restricted antigens. Therefore, we hypothesized that T cells specific for endometrial antigens act as physiological mediators of tissue breakdown, coordinating the timing and extent of endometrial cell death. Methods We integrated 3D volumetric imaging of optically cleared uteri with targeted genetic perturbations, temporally resolved manipulations across the estrous cycle, and adoptive transfer of defined T cell populations. Results We found that a population of conventional CD4+ T cells dynamically traffics from uterus-draining lymph nodes to the endometrium at defined stages of the estrous cycle, where they become locally activated in a TCR-dependent manner. Depletion of commensal microbes did not alter their activation or accumulation, indicating that these responses are most likely driven by self-antigens. Genetic ablation or acute depletion of CD4+ T cells markedly delayed endometrial degradation and disrupted the synchrony of epithelial and stromal cell death. Conclusion Our data identify a controlled autoimmune T cell response as a physiological mechanism that orchestrates the cyclical breakdown of the endometrium. These findings challenge the view of autoimmunity as exclusively pathological and position self-reactivity as an essential component of homeostasis, with broad implications for understanding immune regulation, tissue remodeling, and reproductive health. Funding Source This material is based upon work supported by the National Institute of General Medical Sciences of the National Institutes of Health under award number T32GM007753, the National Science Foundation Career Award, under award number 2442857, and by the National by the Ragon Institute under a Strategic Initiative grant. Any opinion, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation or the National Institutes of Health. Topic Categories Basic Autoimmunity (BA)