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

Area of Science:

• Immunology
• Gastroenterology
• Developmental Biology

Background:

• The fetal immune system is generally tolerogenic, yet preterm infants are susceptible to intestinal inflammation like necrotizing enterocolitis (NEC).
• Understanding the immune cells in the fetal gut is crucial for addressing preterm infant morbidities.

Purpose of the Study:

• To identify and characterize T cells in the human fetal intestine.
• To investigate the role of these T cells in intestinal development and inflammation.

Main Methods:

• Single-cell RNA sequencing of fetal intestinal CD4+ T cells.
• Organoid co-culture models with fetal intestinal CD4+ T cells and intestinal stem cells (ISCs).
• Analysis of T cell populations in NEC infant intestines compared to healthy controls.

Main Results:

• Human fetal intestines harbor a predominant population of tumor necrosis factor-α (TNF-α)+CD4+CD69+ T effector memory (Tem) cells.
• These fetal T cells exhibit a T helper 1 phenotype and express genes supporting epithelial growth and cell cycling.
• Fetal intestinal CD4+ T cells modulate intestinal stem cell (ISC) development in a dose-dependent, TNF-α-mediated manner, supporting growth at low numbers and inhibiting proliferation at high numbers.
• Higher frequencies of CD4+ Tem cells with enhanced TNF signaling were observed in preterm infants with NEC compared to healthy infants.

Conclusions:

• A unique population of TNF-α-producing CD4+ T cells promotes fetal intestinal mucosal development.
• These cells can contribute to intestinal inflammation, particularly in the context of preterm birth and NEC.