High-dimensional immune atlas of second trimester human intestinal immunity

Abstract

Abstract It has long been postulated that newborn’s immune system is immature. To this end, a third of neonatal deaths are due to infections. Similarly, newborns tend to have reduced immune responses to vaccines. Nevertheless, most newborns are healthy. There is limited direct human studies focusing on utero fetal mucosal immune development. Therefore, there is a critical need to investigate fetal mucosal immunity. Using cytometry time of flight (CyTOF) and next-generation sequencing of B and T-cell receptor (B/TCR) repertoires of small (S) and large intestines (LI), we show that intestinal immunity is diverse and functional as early as 16 weeks gestation (GA). Similarly, BCR and TCR repertoires are as diverse in early fetal as in full term samples, though an increase in CDR3β length and distance-from-germline correlates with advanced GA. Innate immunity is dominated by antigen presenting cells, including CD103+DCs, innate lymphoid cells and natural killer cells. B-cells are also present in all tissue examined, with follicular and transitional B-cells enriched in the fetal and CD69+IgM+B-cell in neonatal tissue. Finally, there is high complexity in T-cells, representing >50% of immune cells with similar frequencies at all developmental stages and locations studied. Contrary to our assumption, the majority of T-cells are of central and effector memory subsets. Even more surprisingly, functional tissue resident memory T-cells are abundant and functional in fetal and neonatal samples. Our data provide the foundation for a mucosal immune atlas of second trimester human development and challenge the paradigm that the neonatal immune system is immature, suggesting that development occurs significantly earlier than previously reported.