Format

Send to

Choose Destination
Immunity. 2019 Feb 19;50(2):462-476.e8. doi: 10.1016/j.immuni.2018.12.010. Epub 2019 Feb 12.

Human Fetal TNF-α-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life.

Author information

1
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
2
Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany.
3
Institut für Neuroimmunologie und Multiple Sklerose, Zentrum für Molekulare Neurobiologie Hamburg, Universitätsklinikum Hamburg-Eppendorf, Hamburg 20251, Germany.
4
Division of Pediatrics, Department of Pediatric Gastroenterology, Wilhelmina Children's Hospital, Utrecht University Medical Center, Utrecht University, Utrecht 3584 EA, the Netherlands; Regenerative Medicine Center Utrecht, Utrecht University Medical Center, University of Utrecht, Utrecht 3584 CT, the Netherlands.
5
Department of Clinical Immunology and Rheumatology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Amsterdam Rheumatology & Immunology Center, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
6
Department of General, Visceral, and Thoracic Surgery and I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany; Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
7
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Kiadis Pharma B.V., Amsterdam 1105 BV, the Netherlands.
8
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Pediatric Surgery, Pediatric Surgery Center of Amsterdam, Amsterdam University Medical Center, Amsterdam 1105 AZ, the Netherlands.
9
Department of Pediatric Surgery, Pediatric Surgery Center of Amsterdam, Amsterdam University Medical Center, Amsterdam 1105 AZ, the Netherlands.
10
Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
11
Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
12
Department of General, Visceral, and Thoracic Surgery and I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany; Immunology and Allergy Unit, Department of Medicine Solna, Karolinska Institute, Stockholm 17176, Sweden.
13
Department of Pediatric Surgery, University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
14
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands.
15
Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Center, Vrije Universiteit, Amsterdam 1081 HV, the Netherlands.
16
Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Department of Pediatrics, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam 1105 AZ, the Netherlands; Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg 20251, Germany. Electronic address: madeleine.bunders@leibniz-hpi.de.

Abstract

Although the fetal immune system is considered tolerogenic, preterm infants can suffer from severe intestinal inflammation, including necrotizing enterocolitis (NEC). Here, we demonstrate that human fetal intestines predominantly contain tumor necrosis factor-α (TNF-α)+CD4+CD69+ T effector memory (Tem) cells. Single-cell RNA sequencing of fetal intestinal CD4+ T cells showed a T helper 1 phenotype and expression of genes mediating epithelial growth and cell cycling. Organoid co-cultures revealed a dose-dependent, TNF-α-mediated effect of fetal intestinal CD4+ T cells on intestinal stem cell (ISC) development, in which low T cell numbers supported epithelial development, whereas high numbers abrogated ISC proliferation. CD4+ Tem cell frequencies were higher in inflamed intestines from preterm infants with NEC than in healthy infant intestines and showed enhanced TNF signaling. These findings reveal a distinct population of TNF-α-producing CD4+ T cells that promote mucosal development in fetal intestines but can also mediate inflammation upon preterm birth.

KEYWORDS:

CD4(+) T cells; TNF-α; immune ontogeny; intestinal mucosa; intestinal stem cells; organoid technology; stem cell biology; tissue generation

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center