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小肠上皮内TCRγδ+ T淋巴细胞存在于早产婴儿的肠道中，但在外科坏死性小肠结肠炎中选择性减少。

Small intestinal intraepithelial TCRγδ+ T lymphocytes are present in the premature intestine but selectively reduced in surgical necrotizing enterocolitis.

作者信息

Weitkamp Jörn-Hendrik, Rosen Michael J, Zhao Zhiguo, Koyama Tatsuki, Geem Duke, Denning Timothy L, Rock Michael T, Moore Daniel J, Halpern Melissa D, Matta Pranathi, Denning Patricia W

机构信息

Department of Pediatrics, Vanderbilt University School of Medicine and Monroe Carell Jr. Children's Hospital at Vanderbilt, Nashville, Tennessee, United States of America.

Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, United States of America.

出版信息

PLoS One. 2014 Jun 6;9(6):e99042. doi: 10.1371/journal.pone.0099042. eCollection 2014.

DOI:10.1371/journal.pone.0099042
PMID:24905458
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4048281/
Abstract

BACKGROUND

Gastrointestinal barrier immaturity predisposes preterm infants to necrotizing enterocolitis (NEC). Intraepithelial lymphocytes (IEL) bearing the unconventional T cell receptor (TCR) γδ (γδ IEL) maintain intestinal integrity and prevent bacterial translocation in part through production of interleukin (IL) 17.

OBJECTIVE

We sought to study the development of γδ IEL in the ileum of human infants and examine their role in NEC pathogenesis. We defined the ontogeny of γδ IEL proportions in murine and human intestine and subjected tcrδ-/- mice to experimental gut injury. In addition, we used polychromatic flow cytometry to calculate percentages of viable IEL (defined as CD3+ CD8+ CD103+ lymphocytes) and the fraction of γδ IEL in surgically resected tissue from infants with NEC and gestational age matched non-NEC surgical controls.

RESULTS

In human preterm infants, the proportion of IEL was reduced by 66% in 11 NEC ileum resections compared to 30 non-NEC controls (p<0.001). While γδ IEL dominated over conventional αβ IEL early in gestation in mice and in humans, γδ IEL were preferential decreased in the ileum of surgical NEC patients compared to non-NEC controls (50% reduction, p<0.05). Loss of IEL in human NEC was associated with downregulation of the Th17 transcription factor retinoic acid-related orphan nuclear hormone receptor C (RORC, p<0.001). TCRδ-deficient mice showed increased severity of experimental gut injury (p<0.05) with higher TNFα expression but downregulation of IL17A.

CONCLUSION

Complimentary mouse and human data suggest a role of γδ IEL in IL17 production and intestinal barrier production early in life. Specific loss of the γδ IEL fraction may contribute to NEC pathogenesis. Nutritional or pharmacological interventions to support γδ IEL maintenance in the developing small intestine could serve as novel strategies for NEC prevention.

摘要

背景

胃肠道屏障不成熟使早产儿易患坏死性小肠结肠炎（NEC）。携带非常规T细胞受体（TCR）γδ的上皮内淋巴细胞（IEL）（γδ IEL）维持肠道完整性，并部分通过产生白细胞介素（IL）17来防止细菌移位。

目的

我们试图研究人类婴儿回肠中γδ IEL的发育，并探讨它们在NEC发病机制中的作用。我们确定了小鼠和人类肠道中γδ IEL比例的个体发生情况，并对tcrδ-/-小鼠进行实验性肠道损伤。此外，我们使用多色流式细胞术计算了NEC婴儿和胎龄匹配的非NEC手术对照组手术切除组织中存活IEL（定义为CD3+ CD8+ CD103+淋巴细胞）的百分比以及γδ IEL的比例。

结果

在人类早产儿中，11例NEC回肠切除术的IEL比例与30例非NEC对照组相比降低了66%（p<0.001）。虽然在小鼠和人类妊娠早期γδ IEL比传统的αβ IEL占主导地位，但与非NEC对照组相比，手术NEC患者回肠中的γδ IEL优先减少（降低50%，p<0.05）。人类NEC中IEL的缺失与Th17转录因子视黄酸相关孤儿核激素受体C（RORC）的下调有关（p<0.001）。TCRδ缺陷小鼠表现出实验性肠道损伤的严重程度增加（p<0.05），TNFα表达更高，但IL17A下调。

结论

小鼠和人类的补充数据表明γδ IEL在生命早期IL17产生和肠道屏障形成中起作用。γδ IEL部分的特异性缺失可能导致NEC发病机制。在发育中的小肠中支持γδ IEL维持的营养或药物干预可作为预防NEC的新策略。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb08/4048281/aa5082b65408/pone.0099042.g009.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/fb08/4048281/e80260ddc2b6/pone.0099042.g002.jpg
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