CAREER: Physiological Roles for Autoimmune T cell Responses in Endometrial Turnover

The immune system is designed to protect our bodies from harmful invaders like viruses and bacteria. To do this, one type of immune cell—called a T cell—must be trained to recognize and attack these threats while avoiding the body’s own healthy tissues. This training process is quite good at eliminating T cells that could attack the body—known as self-reactive T cells. However, it is not perfect, and some self-reactive T cells still make it into circulation. Why this system allows these potentially harmful cells to remain has long puzzled scientists. The traditional view holds that self-reactive T cells are dangerous mistakes—usually kept under control, but capable of causing autoimmune disease if regulation fails. This project explores a new idea: that the immune system may tolerate self-reactive T cells for a reason—that, when properly regulated, these cells might help keep tissues healthy. The investigators findings suggest this could be especially true in the uterus, which goes through regular cycles of breakdown and repair during the reproductive years. In this context, self-reactive T cells appear to support tissue remodeling, helping to maintain reproductive health. To further explore this idea, the project combines immunology and systems biology, using advanced imaging, mathematical approaches, and genetic tools to study how self-reactive T cells behave in the uterus. The research should reshape how scientists think about autoimmunity and fertility—and potentially lead to new ways to treat reproductive disorders like endometriosis or infertility. This award was co-funded by the Developmental Systems Cluster. A subset of highly self-reactive T cells persists in the body despite central tolerance mechanisms designed to eliminate them. While these cells are generally considered dangerous, this project presents a new hypothesis: that their persistence reflects a purposeful feature of the immune system—enabling self-reactive T cells, when properly regulated, to support normal tissue physiology. The murine uterus provides an ideal system for evaluating this concept, as its endometrial lining undergoes rapid, cyclical breakdown and regeneration during the estrous cycle—dynamics only partially explained by hormonal signals. The preliminary data reveal that conventional CD4+ T cells accumulate in the endometrium in an oscillatory manner, in phase with the estrous cycle, and become locally activated by endometrial antigens seemingly derived from self proteins. Disruption of these cells perturbs endometrial turnover, suggesting a physiological role for self-reactive T cells in driving endometrial tissue remodeling. To further test this hypothesis, the project will pursue three independent aims: 1) define the antigen specificity and activation triggers of endometrial T cells across the estrous cycle, 2) identify the molecular and cellular mechanisms regulating their accumulation, dynamics, and effector functions, and 3) assess how their dysregulation impacts reproductive hormone dynamics and fertility outcomes. These aims will be addressed through an interdisciplinary approach that combines quantitative in situ multiplexed imaging, mathematical modeling, and genetic perturbations. This research is tightly integrated with an educational initiative to train interdisciplinary scientists at the interface of immunology and systems biology through a new course and PhD program at MIT. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.