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.

尽管胎儿的免疫系统被认为具有耐受性，但早产儿可能患有严重的肠道炎症，包括坏死性小肠结肠炎（NEC）。在这里，我们证明人的胎儿肠道主要包含肿瘤坏死因子-α（TNF-α）⁺ CD4 ⁺ CD69 ⁺ T效应记忆（Tem）细胞。胎儿肠道CD4 ⁺ T细胞的单细胞RNA测序显示T辅助1表型和介导上皮生长和细胞周期的基因表达。类器官共培养显示胎儿肠CD4 ⁺具有剂量依赖性，TNF-α介导的作用T细胞在肠道干细胞（ISC）发育中，其中低T细胞数量支持上皮发育，而高数量则废除了ISC增殖。NEC早产儿发炎小肠的CD4 ⁺ Tem细胞频率高于健康婴儿小肠的CD4 ⁺ Tem细胞频率，并显示出增强的TNF信号传导。这些发现揭示了产生TNF-α的CD4 ⁺ T细胞的独特群体，它们促进胎儿肠道粘膜的发育，但也可以在早产时介导炎症。