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Dev Cell. 2019 Nov 4;51(3):357-373.e5. doi: 10.1016/j.devcel.2019.09.008. Epub 2019 Oct 10.

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

Author information

1
Division of Newborn Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA.
2
Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
3
Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.
4
Pediatric Department A, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Immunology Service, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Jeffrey Modell Foundation Center, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
5
Pediatric Gastroenterology Unit, Edmond and Lily Safra Children's Hospital, Sheba Medical Center, Tel Hashomer 52621, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address: dror.shouval@gmail.com.
6
Division of Newborn Medicine, Department of Pediatrics, UPMC Children's Hospital of Pittsburgh, Pittsburgh, PA 15224, USA; Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA; Department of Developmental Biology, University of Pittsburgh, Pittsburgh, PA 15213, USA. Electronic address: liza.konnikova@chp.edu.

Abstract

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.

KEYWORDS:

BCR; CyTOF; TCR; TRM T cells; development; fetal mucosal immunity; immune repertoire; intestinal immunity; next-generation sequencing

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