Distinct Innate Immune Correlations to Tissue-Resident Memory T Cell Distribution across the Female Reproductive Tract 2259843

Abstract Introduction Tissue resident memory T cells (TRM) positioned within immune-restricted tissue sites, including the female reproductive tract (FRT), are essential contributors to immunity against invading pathogens. Although tissue environments provide homeostatic supports required for TRM maintenance, the mechanisms that regulate immune memory surveillance in distinct regions of the FRT are unclear. Methods Here, we compared cellular and transcriptomic profiles from the different FRT anatomic regions using hysterectomy hemi specimens from healthy donors of reproductive age and known hormonal status. Results We found that the TRM populations exhibited region-specific differences in abundance and phenotype, with overall greater heterogeneities identified in uterine tissue. Correlations between innate cell subsets and TRM properties across FRT compartments were identified with NK cell subtypes and migratory memory T cells, which indicated an association of these populations with endogenous levels of the sex hormone, progesterone. Single-cell RNA sequencing revealed regional changes in TRM transcriptional programming associated with T cell functionality and plasticity. Ex vivo treatment of FRT epithelial cell populations with IFNg showed disparities in response kinetics associated with T cell activation. Conclusion Taken together, this study describes compartmental differences in innate cell contributions to TRM programming that are influenced by sex hormone status. We further identify correlations between distal tissue sites in the FRT that might inform upon uterine health. Funding Source NIH R21AI180610 Topic Categories Mucosal and Regional Immunology (MUC)