An endometrial immune atlas across the female menstrual cycle reveals lymphoid aggregates compromise pregnancy.

The human endometrial immune landscape is critical for homeostasis and pregnancy success, yet its dynamic remodeling across the menstrual cycle and in pathology remains poorly characterized. Here, we construct a comprehensive immune cell atlas of the human endometrium, profiling 53 healthy women and 34 chronic endometritis (CE) patients across precisely staged menstrual cycle phases. Our analysis reveals NK and T cells as dominant constituents, with NK cells increasing while T cells decreasing progressively from proliferative to secretory phase. B cells, mast cells, and innate lymphoid cells remain consistently low. Of the two tissue-resident NK subsets, CD11c⁺ NK cells accumulate during the secretory phase and early pregnancy. CE disrupts this landscape, marked by CD11c⁺ NK cell reduction, local B cell proliferation and differentiation, and formation of ectopic lymphoid aggregates comprising germinal-center-B-like cells and T follicular helper-like cells. Using a murine CE model and a subsequent multi-center cohort study we demonstrate that these aggregates compromise pregnancy outcomes in a Tfh-like-cell-dependent manner. Collectively, we establish a detailed immune cell atlas of the cycling human endometrium and define a pathogenic mechanism for adverse pregnancy outcomes.