Interaction between Batf3 dependent dendritic cells and the microbiota during experimental colitis

肠道微生物的实体，也称为微生物群，发挥关键功能，例如消化特性和维持有利于宿主的屏障完整性。为了控制肠道植物群和宿主细胞之间的密切相互作用，在粘膜表面形成了复杂的免疫网络，以一方面防止微生物群不受控制地传播到肠外，另一方面防止针对非致病性肠道的免疫应答过度。粘液树突状细胞（DC）对产生抗微生物免疫应答和维持肠道内环境稳定至关重要。以前，自己的工作确定了转录因子Batf3作为淋巴驻留CD8 α pos的中央调节器。和粘膜CD 103阳性、CD 11阳性、DC发育。因此，Batf3缺陷型小鼠代表了一种优秀的体内小鼠模型系统，允许分析Batf3依赖性DC在肠道炎症和感染期间的作用。有趣的是，Batf3缺陷小鼠对啮齿类柠檬酸杆菌的肠道感染具有相对抗性，啮齿类柠檬酸杆菌是一种反映人类致病性E.大肠杆菌（例如EHEC）介导的结肠炎。通过长期抗生素治疗的植物群消耗研究的结果表明，在不存在Batf3的情况下，感染抗性主要由预先存在的微生物定殖介导。有趣的是，共同饲养和粪便移植分别能够将针对啮齿类柠檬酸杆菌感染的相对保护从Batf3缺陷小鼠转移到野生型小鼠。来自非感染性实验转移结肠炎模型的数据也证明结肠炎易感性是通过肠道植物群的转移而传染的。通过下一代测序对粪便进行的初步分析表明，与对照组相比，Batf3缺陷与肠道微生物群组成的显著改变有关。这些结果表明，Batf3依赖性DC对肠道菌群的组成和功能有重要影响，并且这种调节似乎可以解释在缺乏Batf3的情况下感染性降低和免疫介导的结肠炎易感性增加的原因。因此，一方面解决Batf3依赖性DC对肠道微生物群组成的贡献的分析，另一方面解决Batf3缺陷小鼠中对啮齿类柠檬酸杆菌的感染抗性的微生物群依赖性免疫效应机制的性质的分析是拟议研究项目的中心。这些研究的结果将为开发有针对性的策略提供基础，以分别有意地调节微生物群和免疫系统的组成或功能，作为肠道感染性和炎症性疾病状态的治疗选择。

The entity of intestinal microbes, also called microbiota, exerts critical functions, e.g. digestive properties and maintenance of barrier integrity in favor of the host. In order to control the close interaction between commensal flora and host cells a sophisticated immunological network has developed at mucosal surfaces to prevent on the one hand uncontrolled dissemination of microbiota beyond the intestine and on the other hand overshooting immune responses against apathogenic commensals. Mucosal dendritic cells (DCs) crucially contribute to the generation of an antimicrobial immune response and the maintenance of gut homeostasis. Previously, own work identified the transcription factor Batf3 as a central regulator of lymphoid resident CD8alphapos. and mucosal CD103pos.CD11bneg.DC development. Batf3 deficient mice therefore represent an excellent in vivo mouse model system allowing the analysis of the role of Batf3 dependent DCs during intestinal inflammation and infections. Interestingly, Batf3 deficient mice are relatively resistant to intestinal infection with Citrobacter rodentium, a rodent pathogen mirroring human pathogenic E. coli (e.g. EHEC) mediated colitis. Results from flora depletion studies via long term antibiotic treatment imply that the infection resistance is predominately mediated by the preexisting microbial colonization in the absence of Batf3. Interestingly cohousing and stool transplantation respectively are able to transfer relative protection against Citrobacter rodentium infection from Batf3 deficient to wildtype mice. Data derived from the noninfectious experimental transfer colitis model also demonstrate that colitis susceptibility is communicable via transfer of the intestinal flora. Preliminary analyses of the stool by next generation sequencing show that Batf3 deficiency is associated with significant alterations of intestinal microbiota composition compared to controls. Together these results show that Batf3 dependent DCs critically influence the composition or function of the gut microbiota and that the modulation seems to account for both the decreased infectious and increased immune-mediated colitis susceptibility in the absence of Batf3.So far studies addressing the consequences of selective DC deficiencies on the composition and function of the intestinal microbiota are limited. Therefore analyses addressing the contribution of Batf3 dependent DCs to the composition of gut microbiota on the one hand and the nature of the microbiota-dependent immunological effector mechanisms underlying the infection resistance against Citrobacter rodentium in Batf3 deficient mice on the other hand are in the center of the proposed research project. Results from these studies will provide the basis to develop targeted strategies to intentionally modulate the composition or function of the microbiota and of the immune system respectively as treatment options of infectious and inflammatory disease states of the gut.