Single-cell atlas of the small intestine throughout the human lifespan demonstrates unique features of fetal immune cells.

Proper development of mucosal immunity is critical for human health. Over the past decade, it has become evident that in humans, this process begins in utero. However, there is limited data on the unique features and functions of fetal mucosal immune cells. To address this gap, we integrated several single-cell RNA sequencing (scRNA-seq) datasets of the human small intestine (SI) to create a SI transcriptional atlas throughout the human life span, ranging from the first trimester to adulthood with a focus on immune cells. Fetal SI displayed a complex immune landscape comprised of both innate and adaptive immune cells, that exhibited distinct transcriptional programs from postnatal samples, especially in comparison to pediatric and adult samples. We identified shifts in myeloid populations across gestation and progression of memory T cell states throughout the human lifespan. In particular, there was a marked shift of memory T cells from those with stem-like properties in the fetal samples to fully differentiated cells with high expression of activation and effector function genes in adult samples with neonatal samples containing both features. Finally, we demonstrate that the SI developmental atlas can be used to elucidate improper trajectories linked to mucosal diseases by implicating developmental abnormalities underlying necrotizing enterocolitis (NEC), a severe intestinal complication of prematurity. Collectively, our data provides valuable resources and important insights into intestinal immunity that will facilitate regenerative medicine and disease understanding.