Maternal microbial exposure fundamentally shapes the CD8 T cell population at the maternal fetal interface

CD8 T cells are potent killers of cells presenting foreign antigens, making them powerful to fight microbial infections. The fetal host immune defense against pathogenic microbes is underdeveloped and ill-equipped to defend against microbial infection and heavily relies on maternal host immune responses to prevent the dissemination of pathogenic microbes. However, the fetus also expresses immunologically foreign allo- antigens, which if recognized by CD8 T cells, could threaten its survival. The maternal-fetal interface (MFI), where fetal and maternal mucosal tissues intertwine, is a critical location for preventing the dissemination of pathogenic microbes and maintaining tolerance for allo-antigens. Major gaps in knowledge relating to CD8 T cell biology, tolerance, and pathology at the MFI have persisted due in large part to necessary restriction on using human cells and tissues for research. In addition, conventional specific pathogen free (SPF) mouse models fail to recapitulate human CD8 T cell biology and diversity, both systemically and in tissues, making them inadequate for studies on CD8 T cells at the MFI. In SPF mice, CD8 T cells make up 0.5-2% of MFI leukocytes and have a naïve phenotype. Conversely, we recently discovered that natural microbial exposure expanded CD8 T cells to 6% of leukocytes at the MFI and phenocopied human CD8 T cells with high fidelity. This proposal uses innovative natural microbial exposure as a more faithful model system of human CD8 T cell biology. Natural microbial exposure expanded CD8 T cell numbers and generated additional CD8 T cell diversity including effector, memory, tissue resident and dysfunctional CD8 T cell types that we also observed at the human MFI. We utilize this model as well as human tissues to gain mechanistic understanding of factors that modulate CD8 T cell tolerance and host immune defense against pathogenic microbes at the MFI. We will compare the immune regulation of CD8 T cells are a result of exposure to a natural microbiome or pathogens both systemically in blood and lymphoid tissues as well as locally in the mucosal tissues. These mechanistic investigations of adaptive CD8 T cell responses will identify tissue localized CD8 T cell types, their receptors and specificity, as well as the beneficial and pathogenic host factors providing immune protection for pathogenic microbes while maintaining immune tolerance. Further, these experiments will lay the groundwork for improved preclinical models investigating biomarkers, treatments, and preventions for immune pathologies at the MFI. Project Number: 1R01AI189469-01 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Nathan Schuldt | Institution: UNIVERSITY OF MINNESOTA, MINNEAPOLIS, MN | Award Amount: $2,999,774 | Activity Code: R01 | Study Section: Immunity and Host Defense Study Section[IHD] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01AI18946901