Brugman Sylvia, Schneeberger Kerstin, Witte Merlijn, Klein Mark R, van den Bogert Bartholomeus, Boekhorst Jos, Timmerman Harro M, Boes Marianne L, Kleerebezem Michiel, Nieuwenhuis Edward E S
a Department of Paediatric Gastroenterology, Wilhelmina Children's Hospital , University Medical Centre Utrecht , Utrecht , The Netherlands.
Gut Microbes. 2014;5(6):737-47. doi: 10.4161/19490976.2014.972228.
Dysbiosis of the intestinal microbial community is considered a risk factor for development of chronic intestinal inflammation as well as other diseases such as diabetes, obesity and even cancer. Study of the innate and adaptive immune pathways controlling bacterial colonization has however proven difficult in rodents, considering the extensive cross-talk between bacteria and innate and adaptive immunity. Here, we used the zebrafish to study innate and adaptive immune processes controlling the microbial community. Zebrafish lack a functional adaptive immune system in the first weeks of life, enabling study of the innate immune system in the absence of adaptive immunity. We show that in wild type zebrafish, the initial lack of adaptive immunity associates with overgrowth of Vibrio species (a group encompassing fish and human pathogens), which is overcome upon adaptive immune development. In Rag1-deficient zebrafish (lacking adaptive immunity) Vibrio abundance remains high, suggesting that adaptive immune processes indeed control Vibrio species. Using cell transfer experiments, we confirm that adoptive transfer of T lymphocytes, but not B lymphocytes into Rag1-deficient recipients suppresses outgrowth of Vibrio. In addition, ex vivo exposure of intestinal T lymphocytes to Rag1-deficient microbiota results in increased interferon-gamma expression by these T lymphocytes, compared to exposure to wild type microbiota. In conclusion, we show that T lymphocytes control microbial composition by effectively suppressing the outgrowth of Vibrio species in the zebrafish intestine.
肠道微生物群落的失调被认为是慢性肠道炎症以及糖尿病、肥胖症甚至癌症等其他疾病发生的一个风险因素。然而，考虑到细菌与固有免疫和适应性免疫之间广泛的相互作用，在啮齿动物中研究控制细菌定植的固有免疫和适应性免疫途径已被证明是困难的。在这里，我们利用斑马鱼来研究控制微生物群落的固有免疫和适应性免疫过程。斑马鱼在生命的最初几周缺乏功能性的适应性免疫系统，这使得在没有适应性免疫的情况下研究固有免疫系统成为可能。我们发现，在野生型斑马鱼中，最初缺乏适应性免疫与弧菌属物种（包括鱼类和人类病原体的一个群体）的过度生长有关，而在适应性免疫发育后这种情况会得到克服。在Rag1缺陷型斑马鱼（缺乏适应性免疫）中，弧菌的丰度仍然很高，这表明适应性免疫过程确实控制着弧菌属物种。通过细胞移植实验，我们证实将T淋巴细胞而非B淋巴细胞移植到Rag1缺陷型受体中可抑制弧菌的生长。此外，与暴露于野生型微生物群相比，肠道T淋巴细胞在体外暴露于Rag1缺陷型微生物群会导致这些T淋巴细胞中γ干扰素表达增加。总之，我们表明T淋巴细胞通过有效抑制斑马鱼肠道中弧菌属物种的生长来控制微生物组成。
