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

Schreurs Renee R. C. E.; Baumdick Martin E.; Sagebiel Adrian F.; Kaufmann Max; Mokry Michal; Klarenbeek Paul L.; Schaltenberg Nicola; Steinert Fenja L.; van Rijn Jorik M.; Drewniak Agata; The Sarah-May M. L.; Bakx Roel; Derikx Joep P. M.; de Vries Niek; Corpeleijn Willemijn E.; Pals Steven T.; Gagliani Nicola; Friese Manuel A.; Middendorp Sabine; Nieuwenhuis Edward E. S.; Reinshagen Konrad; Geijtenbeek Teunis B. H.; van Goudoever Johannes B.; Bunders Madeleine J.

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

机译：人体胎儿TNF-α-细胞因子 - 产生CD4（+）效应记忆T细胞促进生命早期肠道发育和介导炎症

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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-alpha (TNF-alpha)(+)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-alpha-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-alpha-producing CD4(+) T cells that promote mucosal development in fetal intestines but can also mediate inflammation upon preterm birth.

机译：虽然胎儿免疫系统被认为是耐受性的，但早产儿会患有严重的肠炎，包括坏死性小肠结肠炎（NEC）。在这里，我们证明人胎肠道主要含有肿瘤坏死因子-α（TNF-α）（+）CD4（+）CD69（+）T效应记忆记忆（TEM）细胞。胎儿肠CD4（+）T细胞的单细胞RNA测序显示T辅助1辅助1表型和介导上皮生长和细胞循环的基因表达。有机体共培养物揭示了胎儿肠CD4（+）T细胞对肠干细胞（ISC）发育的剂量依赖性TNF-α-介导的效果，其中低于上皮发育的低T细胞数，而耗尽ISC增殖。来自早产儿的CD4（+）TEM细胞频率高于NEC的早产儿比在健康的婴儿肠中，并显示出增强的TNF信号传导。这些发现揭示了促进胎儿肠中粘膜发育的TNF-α（+）T细胞的不同群体，但也可以在早产时介导炎症。

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《Immunity》 |2019年第2期|共23页
作者
Schreurs Renee R. C. E.; Baumdick Martin E.; Sagebiel Adrian F.; Kaufmann Max; Mokry Michal; Klarenbeek Paul L.; Schaltenberg Nicola; Steinert Fenja L.; van Rijn Jorik M.; Drewniak Agata; The Sarah-May M. L.; Bakx Roel; Derikx Joep P. M.; de Vries Niek; Corpeleijn Willemijn E.; Pals Steven T.; Gagliani Nicola; Friese Manuel A.; Middendorp Sabine; Nieuwenhuis Edward E. S.; Reinshagen Konrad; Geijtenbeek Teunis B. H.; van Goudoever Johannes B.; Bunders Madeleine J.;
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作者单位

Univ Amsterdam Amsterdam Univ Med Ctr Amsterdam Infect &

Immun Inst Dept Expt Immunol NL-1105;

Leibniz Inst Expt Virol Heinrich Pette Inst D-20251 Hamburg Germany;

Leibniz Inst Expt Virol Heinrich Pette Inst D-20251 Hamburg Germany;

Univ Klinikum Hamburg Eppendorf Zentrum Mol Neurobiol Hamburg Inst Neuroimmunol &

Multiple;

Univ Utrecht Med Ctr Wilhelmina Childrens Hosp Div Pediat Dept Pediat Gastroenterol NL-3584 EA;

Univ Amsterdam Amsterdam Univ Med Ctr Amsterdam Infect &

Immun Inst Dept Expt Immunol NL-1105;

Univ Med Ctr Hamburg Eppendorf Dept Gen Visceral &

Thorac Surg D-20246 Hamburg Germany;

Leibniz Inst Expt Virol Heinrich Pette Inst D-20251 Hamburg Germany;

Univ Utrecht Med Ctr Wilhelmina Childrens Hosp Div Pediat Dept Pediat Gastroenterol NL-3584 EA;

Univ Amsterdam Amsterdam Univ Med Ctr Amsterdam Infect &

Immun Inst Dept Expt Immunol NL-1105;

Univ Amsterdam Amsterdam Univ Med Ctr Amsterdam Infect &

Immun Inst Dept Expt Immunol NL-1105;

Amsterdam Univ Med Ctr Pediat Surg Ctr Amsterdam Dept Pediat Surg NL-1105 AZ Amsterdam;

Amsterdam Univ Med Ctr Pediat Surg Ctr Amsterdam Dept Pediat Surg NL-1105 AZ Amsterdam;

Univ Amsterdam Amsterdam Univ Med Ctr Amsterdam Infect &

Immun Inst Dept Expt Immunol NL-1105;

Univ Amsterdam Amsterdam Univ Med Ctr Emma Childrens Hosp Dept Pediat NL-1105 AZ Amsterdam;

Univ Amsterdam Amsterdam Univ Med Ctr Dept Pathol NL-1105 AZ Amsterdam Netherlands;

Univ Med Ctr Hamburg Eppendorf Dept Gen Visceral &

Thorac Surg D-20246 Hamburg Germany;

Univ Klinikum Hamburg Eppendorf Zentrum Mol Neurobiol Hamburg Inst Neuroimmunol &

Multiple;

Univ Utrecht Med Ctr Wilhelmina Childrens Hosp Div Pediat Dept Pediat Gastroenterol NL-3584 EA;

Univ Utrecht Med Ctr Wilhelmina Childrens Hosp Div Pediat Dept Pediat Gastroenterol NL-3584 EA;

Univ Med Ctr Hamburg Eppendorf Dept Pediat Surg D-20246 Hamburg Germany;

Univ Amsterdam Amsterdam Univ Med Ctr Amsterdam Infect &

Immun Inst Dept Expt Immunol NL-1105;

Univ Amsterdam Amsterdam Univ Med Ctr Emma Childrens Hosp Dept Pediat NL-1105 AZ Amsterdam;

Univ Amsterdam Amsterdam Univ Med Ctr Amsterdam Infect &

Immun Inst Dept Expt Immunol NL-1105;

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正文语种 eng
中图分类医学免疫学;
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1. Human Fetal TNF-alpha-Cytokine-Producing CD4(+) Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life [J] . Schreurs Renee R. C. E., Baumdick Martin E., Sagebiel Adrian F., Immunity . 2019,第2期

机译：人体胎儿TNF-α-细胞因子 - 产生CD4（+）效应记忆T细胞促进生命早期肠道发育和介导炎症
2. IL-1β mediates chronic intestinal inflammation by promoting the accumulation of IL-17A secreting innate lymphoid cells and CD4+ Th17 cells [J] . Margherita Coccia, Oliver J. Harrison, Chris Schiering, The Journal of Experomental Medicine . 2012,第9期

机译：IL-1β通过促进分泌IL-17A的先天淋巴样细胞和CD4 + Th17细胞的蓄积来介导慢性肠道炎症
3. Human CD4+ central and effector memory T cells produce IL-21: effect on cytokine-driven proliferation of CD4+ T cell subsets. [J] . Onoda T, Rahman M, Nara H, International immunology. . 2007,第10期

机译：人CD4 +中枢和效应记忆T细胞产生IL-21：对细胞因子驱动的CD4 + T细胞亚群增殖的影响。
4. Oral administration of food antigen induces T cell mediated intestinal inflammation: A model using TCR-transgenic mice [C] . Akira Kikuchi, Haruyo Nakajima-Adachi, Ayumi Ebihara, International Conference on Food Factors . 2004

机译：食物抗原的口服给药诱导T细胞介导的肠炎：使用TCR转基因小鼠的模型
5. Mechanisms for 2,3,7,8-tetrachlorodibenzo-p-dioxin-mediated effects on CD40 ligand-induced activation and effector function of primary human and mouse B cells [D] . Lu, Haitian 2010

机译：2,3,7,8-四氯二苯并-p-二恶英介导的对CD40配体诱导的人和小鼠B细胞活化和效应子功能的作用机理
6. Lung effector memory and activated CD4+ T cells display enhanced proliferation in SP-A-deficient mice during allergen-mediated inflammation [O] . Amy M. Pastva, Sambuddho Mukherjee, Charles Giamberardino, -1

机译：肺效应记忆和活化CD4 + T细胞显示过敏原介导的炎症期间SP-A缺陷小鼠的增强增殖
7. Human Fetal TNF-α-Cytokine-Producing CD4+ Effector Memory T Cells Promote Intestinal Development and Mediate Inflammation Early in Life [O] . Renée R.C.E. Schreurs, Martin E. Baumdick, Adrian F. Sagebiel, 2019

机译：人体胎儿TNF-α-细胞因子 - 产生CD4 +效应记忆记忆T细胞促进生命早期肠道发育和介导炎症

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

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