Regional and Hormone-Associated Adaptations of Tissue-Resident Memory T cells across the Human Female Reproductive Tract.

Abstract Tissue-resident memory T cells (TRM) are essential components of mucosal immunity, yet their organization and regulation across the human female reproductive tract (FRT) remain poorly understood. Here, we investigated TRM across the FRT from donors with diverse hormonal profiles and identified regional and lineage-specific differences in phenotype, transcriptional programming, and abundance. CD8 T cells displayed greater enrichment of canonical TRM signatures and extensive T cell receptor clonal sharing across tissues, suggesting a common antigenic immune history. Despite these differences, resident CD4 and CD8 T cells shared CCR5 protein expression and TSC22D3 transcript enrichment, highlighting potentially distinctive features of FRT TRM. Single-cell transcriptomics revealed compartmental differences in metabolic, stress- and hormone-response pathways. Progesterone and testosterone levels were associated with differences in cervical T cell composition and CD8 TRM abundance. Together, these findings describe regional specialization by resident T cell immunity across the FRT and show that hormonal cues contribute to their homeostasis, offering new insight into factors that shape immune surveillance at mucosal sites of urogenital pathogen exposure.