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

肠道微生物的实体，也称为微生物区系，发挥着关键功能，如消化特性和维持有利于宿主的屏障完整性。为了控制共生菌群和宿主细胞之间的密切相互作用，在粘膜表面形成了一个复杂的免疫网络，一方面防止微生物区系不受控制地扩散到肠道以外，另一方面防止对非致病共生菌的免疫反应。粘膜树突状细胞(DC)在产生抗微生物免疫反应和维持肠道内环境稳定方面起着至关重要的作用。此前，OWN的工作确定转录因子BATF3是淋巴驻留CD8alphapos的中央调节因子。粘膜CD103pos.CD11beg.DC发育。因此，BATF3缺陷小鼠是一个很好的体内小鼠模型系统，可以分析依赖BATF3的DC在肠道炎症和感染中的作用。有趣的是，BATF3缺陷小鼠对肠道感染轮状柠檬酸杆菌具有相对的抵抗力，这是一种反映人类致病性大肠杆菌(如EHEC)介导的结肠炎的啮齿动物病原体。通过长期抗生素治疗的菌群枯竭研究结果表明，在没有BATF3的情况下，感染耐药性主要是由预先存在的微生物定植介导的。有趣的是，共居和粪便移植分别能够将对轮状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。来自非感染性实验性转移性结肠炎模型的数据也表明，结肠炎易感性是通过肠道菌群转移而传染的。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缺乏与肠道微生物区系组成的显著变化有关。综上所述，这些结果表明，依赖于BATF3的DC对肠道微生物区系的组成或功能具有关键影响，这种调节似乎解释了在没有BATF3的情况下，感染性结肠炎易感性降低和免疫介导的结肠炎易感性增加的原因。到目前为止，关于选择性DC缺乏对肠道微生物区系组成和功能的影响的研究有限。因此，一方面分析BATF3依赖的DC对肠道微生物区系组成的贡献，另一方面分析BATF3缺陷小鼠对轮状柠檬酸杆菌感染的抵抗力所依赖的微生物区系免疫效应机制的性质，这是拟议的研究项目的中心。这些研究的结果将为制定有针对性的战略提供基础，以有目的地分别调节微生物区系和免疫系统的组成或功能，作为肠道传染病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.