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

IL-10是黏膜免疫系统中一种重要的调节细胞因子，IL-10缺乏的小鼠会自发发展为克罗恩病样结肠炎，这一事实得到了支持。一种异常的，Th1驱动的CD4^+T细胞对肠道细菌的反应似乎在这种小鼠结肠炎的发病机制中很重要。然而，目前还没有鉴定出特定的细菌或细菌产物，结肠炎是否由识别特定多肽-MHC复合体的CD4^+T细胞激活所介导，仍存在争议。在本研究中，我们用免疫显微镜技术分析了IL-10缺陷小鼠结肠β^+T细胞的TCRCDR3链。对白介素10缺陷病小鼠的筛查导致TCRVCD413和14个结肠β^+T细胞亚家族出现限制性克隆型。相反，外周淋巴组织中单个TCRVβ亚群的克隆型呈正态分布。虽然个别的…在拉荷亚和大阪保存的其他IL-10缺陷小鼠中，也发现了更多与疾病相关的L变异，可能是由于疾病的不同阶段、遗传背景或居住环境，所有受试疾病小鼠似乎都有与结肠炎相关的公共克隆。为了确定是否涉及公共克隆，我们测定了这些克隆的DNA序列。不同背景的IL-10缺陷结肠炎小鼠的结肠CD_4~+T细胞具有相同的公共模体。最常见的基序是SXDWG和SATGNYAEQ。在患病小鼠的外周淋巴组织和未患病小鼠的结肠中没有发现这些基序。因此，共同的基序可能与一个公共肠源性抗原有关，这可能对该IBD模型中致病的CD4^+T细胞的发展起重要作用。在单个小鼠中，Vβ-Jβ的选择可能是随机的；然而，重组机制产生的SXDWG基序以及在肠道环境中对该基序的选择可能对触发IBD很重要。较少

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