Human fetal small intestinal T cells induce epithelial growth and secretory lineage differentiation 2280

Abstract Description The fetal immune system was classically believed to be immature to prevent fetal rejection. However, it is highly dynamic and compartmentalized with functional mucosal T cells dominating the fetal small intestine (SI) in the second trimester of pregnancy. The roles of SI T cells during early human development are not well defined, but we hypothesize that mucosal T cells perform homeostatic functions in epithelial growth and differentiation. To test this, we generated an organoid-immune co-culture system to investigate cellular crosstalk during development. To this end, we performed donor-matched and -unmatched T cell-organoid co-cultures with organoids and T cells derived from the SI of fetal and adult donors. Fetal SI T cells significantly promoted organoid growth. Surprisingly, using single-cell RNA sequencing we found that fetal T cells also directed differentiation towards secretory epithelial cell fates (i.e., goblet, enteroendocrine, tuft, and Paneth cells). In contrast, adult T cells did not support organoid growth above the control conditions, highlighting specialized roles of perinatal T cells. Together, these data suggest that early life SI T cells perform critical homeostatic functions in epithelial development, possibly to prepare the gut for postnatal life by inducing cell types required for host defense or hormonal regulation. Whether these roles are dysregulated in preterm intestinal pathologies, such as necrotizing enterocolitis, warrants further exploration. Funding Sources Supported by NIH AI171980; NIH P30DK034854-36; YSM Science Fellows 2024 Grant; Yale School of Medicine Departments of Immunobiology and Pediatrics Topic Categories Mucosal and Regional Immunology (MUC)