Natural microbial exposure populates the maternal fetal interface with diverse T cells

Amy Whillock¹Perianne Smith²Sarah Burger¹Adhvaith Sridhar³Alex Lindgren³James Berg^4,5Sayaka Tsuda^6,7Shweta Mahajan^6,8Tamara Tilburgs^6,8,9*Nathaniel J Schuldt^1,10,11,2*

• ¹Department of Pediatrics, Medical School, University of Minnesota, Minneapolis, Minnesota, United States
• ²Microbiology, Immunology, and Cancer Biology, University of Minnesota, Minneapolis, United States
• ³College of Biological Sciences, University of Minnesota, Minnesota, Minnesota, United States
• ⁴College of Veterinary Medicine, University of Minnesota, St Paul, Minnesota, United States
• ⁵Comparative and Molecular Biosciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, United States
• ⁶Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States
• ⁷Department of Obstetrics and Gynecology, Faculty of Medicine, University of Toyama, Toyama, Japan
• ⁸Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
• ⁹Center for Inflammation and Tolerance, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States
• ¹⁰Center for Immunology, Medical School, University of Minnesota, Minneapolis, Minnesota, United States
• ¹¹Masonic Cancer Center, Medical School, University of Minnesota, Minneapolis, Minnesota, United States

Diverse T cell types accumulate at the human maternal fetal interface (MFI) during pregnancy to orchestrate immune tolerance for foreign fetal/placental tissues and immunity to pathogens. Yet, the dynamics of T cell influx and function at the MFI remain poorly defined. Conventional specific pathogen free (SPF) murine models fail to replicate the number and diversity of T cells in the human MFI, hindering mechanistic study of MFI T cells. Here we present an innovative use of a natural microbial exposure (NME) mouse model that enhances T cell influx and diversity in the MFI. We defined changes in the MFI of NME mice, relative to SPF mice and human tissues using transcriptomic and proteomic approaches. Physiological maternal microbial burden reproduced key features of human MFI immunology by i) significantly increasing the numbers and diversity of CD4 and CD8 effector and memory T cells at the MFI; ii) skewing the CD8 T cell composition towards tissue resident memory phenotypes with increased signatures of activation and dysfunction similar to human decidual T cells; and iii) expanding unconventional γδ T cells and Killer Lectin-like Receptors (KLR) expressing T cell types at the MFI, representative of an enhanced ability to interact with placental trophoblasts or infected cells. Thus, maternal microbial exposure induces vast changes to T cell numbers, diversity and functions at the MFI that models human MFI T cells with great fidelity. The NME model allows for improved translational investigation of the mechanisms of T cell tolerance, immunity, and inflammation in pregnancy.