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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Female
  • Fetus / immunology*
  • Fetus / metabolism
  • Humans
  • Immunologic Memory / immunology*
  • Infant, Newborn
  • Intestinal Mucosa / embryology
  • Intestinal Mucosa / growth & development
  • Intestinal Mucosa / immunology
  • Intestines / embryology
  • Intestines / growth & development
  • Intestines / immunology*
  • Mice, Inbred C57BL
  • Pregnancy
  • Stem Cells / cytology
  • Stem Cells / immunology
  • Stem Cells / metabolism
  • Th1 Cells / immunology
  • Th1 Cells / metabolism
  • Tumor Necrosis Factor-alpha / immunology*
  • Tumor Necrosis Factor-alpha / metabolism


  • Tumor Necrosis Factor-alpha