Enhanced TH17 Responses in Patients with IL10 Receptor Deficiency and Infantile-onset IBD
Enhanced TH17 Responses in Patients with IL10 Receptor Deficiency and Infantile-onset IBD
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DOI：
10.1097/mib.0000000000001270
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发表时间：
2017-11-01
影响因子：
4.9
通讯作者：
Snapper, Scott B.
中科院分区：
文献类型：
--
作者：
Shouval, Dror S.;Konnikova, Liza;Snapper, Scott B.
背景：IL10受体（IL10R）缺乏导致严重的婴儿期炎症性肠病。完整的il10r依赖信号已被证明对小鼠先天和适应性免疫细胞功能很重要。我们之前报道了il - 10在人类抗炎巨噬细胞的产生和功能中的关键作用。独立于先天免疫细胞缺陷，本研究的目的是确定IL10R信号在调节人类CD4+ t细胞功能中的作用。方法：采集IL10/ il10r缺陷患者和对照组的外周血单个核细胞和肠活检细胞。通过流式细胞术检测CD4+ T细胞亚群频率、初始T细胞增殖频率、调节性T细胞（Treg）介导的抑制频率以及Treg和TH17的生成频率。通过NanoString和实时定量聚合酶链反应进行转录谱分析。采用RNA原位杂交法测定肠黏膜中各种转录本的数量。结果：16例il10和il10r缺陷患者的分析显示，与对照组相比，外周血和肠道Tregs的频率相似。此外，在体外，Treg抑制CD4+ t细胞增殖和Treg的产生不依赖于IL10R信号。然而，与对照组相比，il10r缺陷的T幼稚细胞表现出更高的增殖能力，强烈的TH17特征，以及对TH17细胞的极化增加。此外，在il10r缺陷患者的结肠和回肠中，TH17细胞的频率增加。最后，我们发现在IL1b存在的情况下刺激il10r缺陷Tregs导致IL17A的产生增强。结论：在人体内，IL10R信号调节TH17极化和t细胞增殖，但对于Tregs的产生和体外抑制不是必需的。靶向TH17轴的治疗可能对IL10-和il10r缺陷患者有益，作为异基因造血干细胞移植的桥梁。
Background: IL10 receptor (IL10R) deficiency causes severe infantile-onset inflammatory bowel disease. Intact IL10R-dependent signals have been shown to be important for innate and adaptive immune cell functions in mice. We have previously reported a key role of IL10 in the generation and function of human anti-inflammatory macrophages. Independent of innate immune cell defects, the aim of the current study was to determine the role of IL10R signaling in regulating human CD4+ T-cell function.Methods: Peripheral blood mononuclear cells and intestinal biopsies cells were collected from IL10/IL10R-deficient patients and controls. Frequencies of CD4+ T-cell subsets, naive T-cell proliferation, regulatory T cell (Treg)-mediated suppression, and Treg and TH17 generation were determined by flow cytometry. Transcriptional profiling was performed by NanoString and quantitative real-time polymerase chain reaction. RNA in situ hybridization was used to determine the quantities of various transcripts in intestinal mucosa.Results: Analysis of 16 IL10-and IL10R-deficient patients demonstrated similar frequencies of peripheral blood and intestinal Tregs, compared with control subjects. In addition, in vitro Treg suppression of CD4+ T-cell proliferation and generation of Treg were not dependent on IL10R signaling. However, IL10R-deficient T naive cells exhibited higher proliferative capacity, a strong TH17 signature, and an increase in polarization toward TH17 cells, compared with controls. Moreover, the frequency of TH17 cells was increased in the colon and ileum of IL10R-deficient patients. Finally, we show that stimulation of IL10R-deficient Tregs in the presence of IL1b leads to enhanced production of IL17A.Conclusions: IL10R signaling regulates TH17 polarization and T-cell proliferation in humans but is not required for the generation and in vitro suppression of Tregs. Therapies targeting the TH17 axis might be beneficial for IL10- and IL10R-deficient patients as a bridge to allogeneic hematopoietic stem cell transplantation.