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Molecular biology of extrathymic T cells for the development of mucosal inflammation

胸腺外 T 细胞在粘膜炎症发展中的分子生物学

基本信息

批准号：
12670303
负责人：
TAKAHASHI Ichiro
金额：
$ 2.43万
依托单位：
OSAKA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12670303/
关键词：
MUCOSAL IMMUNOLOGY EXTRATHYMIC T CELLS INFLAMMATION CROHN'S DISEASE PUBLIC CDR3 MOTIF T細胞炎症性腸疾患

项目摘要

IL-10 is an important regulatory cytokine in the mucosal immune system, as supported by the fact that mice deficient in IL-10 spontaneously develop Crohn's disease-like colitis. An aberrant, Th1-driven CD4^+ T-cell response to enteric bacteria seems to be important in the pathogenesis of this murine colitis. However, no specific bacteria or bacterial products have been identified, whether the colitis is mediated by the activation of CD4^+ T cells that recognize specific peptide-MHC complexes is controversial. In this study, we analyzed the TCRβ chain CDR3 length spectratype of colonic CD4^+ T cells isolated from diseased IL-10-deficient mice by using the Immunoscope technique. Screening of the diseased interleukin-10 deficient mice resulted in a restricted clonotype in TCR Vβ 13 and 14 subfamilies of colonic CD4^+ T cells. In contrast, a Gaussian distribution of clonotype of individual TCR Vβ subsets was observed in CD4^+ T cells from the peripheral lymphoid tissues. Although individua … More l variability in the disease-related response was also noted in other IL-10-deficient mice maintained in La Jolla and Osaka, perhaps because of different stages of the disease, genetic background, or the housing environment, colitis-related public clones seemed to be shared in all the tested diseased mice. To address whether public clones were involved, we determined DNA sequence of the clones. Public motifs were shared in colonic CD4^+ T cells from different background interleukin-10 deficient mice with colitis. The frequently found motifs were SXDWG and SATGNYAEQ. These motifs were not seen in the peripheral lymphoid tissues of diseased mice as well as the colon of nondiseased mice. Thus, the common motif may be related to a public gut-derived antigen, which could be important for the development of pathogenic CD4^+ T cells in this IBD model. The selection of Vβ-Jβ usage is perhaps stochastic in individual mice ; however, the epigenetic generation of SXDWG motif by the recombination machinery and selection for this motif in the gut environment could be : important for triggering IBD. Less

IL-10 是粘膜免疫系统中重要的调节细胞因子，缺乏 IL-10 的小鼠会自发患上克罗恩病样结肠炎，这一事实证明了这一点。 Th1 驱动的 CD4^+ T 细胞对肠道细菌的异常反应似乎在这种小鼠结肠炎的发病机制中很重要。然而，尚未鉴定出特定的细菌或细菌产物，结肠炎是否是由识别特定肽-MHC复合物的CD4+T细胞的激活介导的仍存在争议。在本研究中，我们使用免疫镜技术分析了从患病IL-10缺陷小鼠中分离出的结肠CD4+T细胞的TCRβ链CDR3长度谱类型。对患病的白细胞介素 10 缺陷小鼠的筛选导致结肠 CD4^+ T 细胞的 TCR Vβ 13 和 14 亚家族的限制性克隆型。相反，在来自外周淋巴组织的 CD4^+ T 细胞中观察到各个 TCR Vβ 亚群的克隆型呈高斯分布。尽管在拉霍亚和大阪饲养的其他 IL-10 缺陷小鼠中也注意到疾病相关反应的个体差异，可能是由于疾病阶段、遗传背景或饲养环境的不同，但结肠炎相关的公共克隆似乎在所有测试的患病小鼠中都有所共有。为了确定是否涉及公共克隆，我们确定了克隆的 DNA 序列。来自不同背景的白细胞介素10缺陷型结肠炎小鼠的结肠CD4+T细胞具有相同的公共基序。常见的图案是 SXDWG 和 SATGNYAEQ。在患病小鼠的外周淋巴组织以及未患病小鼠的结肠中没有发现这些基序。因此，共同基序可能与公共肠道衍生抗原有关，这对于 IBD 模型中致病性 CD4^+ T 细胞的发育可能很重要。 Vβ-Jβ 使用的选择在个体小鼠中可能是随机的；然而，通过重组机制产生 SXDWG 基序的表观遗传以及在肠道环境中对该基序的选择可能：对于触发 IBD 很重要。较少的