Molecular analysis of the immune-modulatory properties of colitogenic intestinal microbiota

致结肠炎肠道微生物群免疫调节特性的分子分析

• 批准号: 316022883
• 负责人: Professor Dr. Kai Hildner
• 金额: --
• 依托单位: Medizinische Klinik 1 - Gastroenterologie, Pneumologie und Endokrinologie
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 财政年份: 2016
• 资助国家: 德国
• 起止时间: 2015-12-31 至 2020-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/316022883?language=en
• 关键词: Molecular; analysis; immune; modulatory; properties

Batf3 (Basic leucin zipper transcription factor, ATF-like 3) -deficient mice allow studies to assess the specific role of related CD8alpha positive and CD103 positive CD11b negative dendritic cells (DCs) in vivo. Our studies unambiguously revealed a colitis-protective role of Batf3 in the T cell transfer-mediated but not in the Dextran sodiume sulphate (DSS)-induced and anti-CD40-mediated colitis model. Co-housing experiments demonstrated that enhanced transfer colitis susceptibility was transmittable to Batf3-expressing wild type mice and even to Rag1-/- IRF4 (interferon regulatory factor 4)-/- mice usually per se refractory to colitis induction. Also, IL-23R-deficient Tcells normally devoid of colitis-promoting abilities induced colitis in the presence of Batf3-deificiency associated microbiota collectively indicating a dominant functional role of the intestinal microbiota within Batf3-deficient mice in promoting colitis. Finally, the existence of a transmittable dysbiosis in Batf3-deficient mice was formally confirmed by 16s ribosomal RNA gene sequencing analyses. Together, Batf3-dependent DCs appear to be crucial regulators of the intestinal microbiota with tremendous implications for colitis susceptibility and phenotype.Based on our data, we propose the follwoing model. The absence of Batf3-dependent DCs presumably promotes the occurrence of so called pathobionts within the intestinal microbiota that drive T cell and myeloid cell expansion. Specifically, we hypothesize that these communities provide either directly or indirectly (e.g. by inhibiting protective signals derived from other commensals) signals that act in an immune-stimulatory fashion creating an immunological microenvironment that promotes detrimental immune-mediated colitis formation. In the center of the proposed studies is therefore the identification of the colitis-promoting microbial communities, their employed molecular signaling armamentarium, the identification and characterization of the host-derived, microbial signal-receiving machinery and of the cellular and molecular immunological effector mechanisms mediating the detrimental colitis manifestation in the presence of Batf3 deficiency-associated intestinal microbiota.

Batf3（碱性亮氨酸拉链转录因子，ATF 样 3）缺陷小鼠允许研究评估相关 CD8α 阳性和 CD103 阳性 CD11b 阴性树突细胞 (DC) 在体内的具体作用。我们的研究明确揭示了 Batf3 在 T 细胞转移介导的结肠炎保护作用中的作用，但在右旋糖酐硫酸钠 (DSS) 诱导的和抗 CD40 介导的结肠炎模型中则不然。共同饲养实验表明，增强的转移性结肠炎易感性可传染给表达 Batf3 的野生型小鼠，甚至传染给 Rag1-/- IRF4（干扰素调节因子 4）-/- 小鼠，这些小鼠本身通常难以诱导结肠炎。此外，IL-23R 缺陷型 T 细胞通常缺乏促进结肠炎的能力，但在存在 Batf3 缺陷相关微生物群的情况下会诱发结肠炎，这表明 Batf3 缺陷型小鼠的肠道微生物群在促进结肠炎中发挥着主导功能作用。最后，16s 核糖体 RNA 基因测序分析正式证实了 Batf3 缺陷小鼠中存在可传播的生态失调。总之，Batf3 依赖性 DC 似乎是肠道微生物群的关键调节因子，对结肠炎易感性和表型具有巨大影响。根据我们的数据，我们提出以下模型。 Batf3 依赖性 DC 的缺失可能会促进肠道微生物群中所谓病原体的出现，从而驱动 T 细胞和骨髓细胞扩张。具体来说，我们假设这些群落直接或间接地提供（例如通过抑制来自其他共生体的保护性信号）信号，这些信号以免疫刺激方式起作用，创造出促进有害的免疫介导的结肠炎形成的免疫微环境。因此，拟议研究的核心是鉴定促进结肠炎的微生物群落、它们所使用的分子信号传导设备、鉴定和表征宿主来源的微生物信号接收机制以及在存在 Batf3 缺陷相关肠道微生物群的情况下介导有害结肠炎表现的细胞和分子免疫效应机制。