Maturation of the Human Intestinal Immune System Occurs Early in Fetal Development

There are limited data on fetal and early life development of human intestinal immunity. Using mass cytometry (CyTOF) and next-generation sequencing of B and T cell receptor (BCR and TCR) repertoires, we demonstrate complex intestinal immunity from 16 weeks' gestational age (GA). Both BCR and TCR repertoires are diverse with CDRH and CDR3β length increasing with advancing GA. The difference-from-germline, CDR insertions and/or deletions, similarly occur in utero for TCR but not BCR, suggesting earlier mucosal T than B cell maturity. Innate immunity is dominated by macrophages, dendritic cells (DCs), innate lymphoid cells (ILCs), and natural killer (NK) cells. Follicular and transitional B cells are enriched in fetuses while CD69⁺IgM⁺ B cells are abundant in infants. Both CD4⁺ and CD8⁺ T cells are abundant, capable of secreting cytokines and are phenotypically of the tissue resident memory state in utero. Our data provide the foundation for a 2nd trimester and infant intestinal immune atlas and suggest that a complex innate and adaptive immune landscape exists significantly earlier than previously reported.