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.
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)CD4CD69 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，但早产儿仍可能遭受严重的肠道炎症，包括坏死性小肠结肠炎（NEC）。在这里，我们证明人类胎儿肠道主要含有肿瘤坏死因子-α（TNF-α）CD4CD69 T 效应记忆（Tem）细胞。对胎儿肠道 CD4 T 细胞的单细胞 RNA 测序显示出辅助性 T 细胞 1 表型和介导上皮生长和细胞周期的基因表达。类器官共培养揭示了胎儿肠道 CD4 T 细胞对肠道干细胞（ISC）发育的剂量依赖性、TNF-α介导的效应，其中低数量的 T 细胞支持上皮发育，而高数量的 T 细胞则破坏 ISC 增殖。与健康婴儿的肠道相比，患有 NEC 的早产儿炎症肠道中的 CD4 Tem 细胞频率更高，并且 TNF 信号转导增强。这些发现揭示了一种独特的 TNF-α产生 CD4 T 细胞群体，它可以促进胎儿肠道的黏膜发育，但也可以在早产时介导炎症。
