Maternal natural microbial exposure in mice increases CD8 T cell heterogeneity at the maternal-fetal interface (MFI) phenocopying the human MFI 3993

Abstract Description During healthy human pregnancies, CD8 T cells accumulate at the MFI becoming the most abundant immune cell late in the third trimester. The majority of human decidual CD8 T cells are memory cells, displaying a mixed signature of dysfunction and activation. Despite the potential threat these cells pose to pregnancy, their function and regulation at the MFI remains poorly defined. In contrast to humans, conventional special pathogen free (SPF) mice have few MFI T cells and generally display a naïve phenotype. The lack of an animal model that recapitulates human immunology has been a barrier to studying the function of CD8 T cells at the MFI. Here, we use a pet-store co-housing mouse model to investigate the impact of maternal natural microbial exposure (NME) on the immunology of the MFI. We found NME increased the number of MFI T cells, particularly CD8 T cells, and increased memory and effector memory cells relative to SPF dams. High-dimensional flow cytometric characterization showed that NME-induced MFI CD8 T cells are a distinct population from circulating blood maternal CD8 T cells. Utilizing single-cell RNA sequencing, we found NME induced ‘resident’ and ‘activation/dysfunction’ transcriptomic phenotypes and an expansion of ‘innate-like’ MFI CD8 T cells, phenocopying human decidual CD8 T cells. Overall, NME mice model human MFI immunology more accurately and can reveal novel insights into the mechanisms that balance tolerance and host defense at the MFI. Funding Sources Supported by: 1R01HD113192-01 NIH (NICHD); Masonic Cross-Departmental Grant in Children’s Health Research; Department of Pediatrics Research Council, Pediatrics “R” Award; Medical School/University of Minnesota Foundation Faculty Research Award; University of Minnesota Pediatric Physician Scientist Training Program Topic Categories Mucosal and Regional Immunology (MUC)