Epithelial antigen presentation in regulation of the host-microbiota relationship

项目摘要 尽管肠道免疫和微生物群之间存在明确的联系，但调节宿主免疫的机制 对肠道微生物的反应仍然知之甚少。肠上皮细胞（IEC）位于 微生物群和动态免疫细胞之间的界面，因此独特地准备校准宿主细胞。 免疫力尽管IEC可能对于破译有害与无害抗原以及指导免疫治疗至关重要， 适当的免疫反应，对IEC调节宿主免疫反应的机制知之甚少。 微生物群的相互作用抗原递呈细胞（APC）必须区分无害和有害 抗原和协调适当的T细胞反应。虽然是非典型的APC，但我的初步数据表明， IEC是肠中最丰富的表达MHCII的细胞，并且IEC中的MHCII表达直接影响肠组织的生长。 被微生物群上调因此，我假设上皮抗原呈递可能是至关重要的， 介导宿主-微生物群相互作用，影响肠道内稳态和炎症。概述的研究 该建议将通过定义IEC-内在MHCII的功能来直接检验该假设。采用最新 开发了突变小鼠品系，肠道类器官，并建立了肠道炎症模型， 提出了具体的目标，将确定（i）IEC-内在MHCII表达对粘膜的影响， 屏障功能和免疫稳态以及（ii）IEC-内在MHCII如何调节肠上皮细胞的发育 炎症总之，这些研究将为微生物群如何指导肠道免疫提供新的见解 并将指导研究和治疗肠道炎性疾病的新方法。 在我过去的研究经历中，我发现了我对宿主-微生物群关系的浓厚兴趣。 出于这个原因，我与Theresa Alenghat博士发起了拟议的项目，该项目将建立在我对 先天免疫和抗原呈递，使我能够过渡到粘膜免疫学领域。我 论文工作为我提供了宿主-病原体相互作用，微生物学和 免疫学，但我以前没有接触过上皮调节，抗原特异性技术， 肠道疾病模型。我的导师Alenghat博士和Sing Sing Way博士的实验室，沿着 辛辛那提儿童医院的特殊科学和知识环境将使我能够利用 现代，创新的方法在我的研究，并与顶级研究人员合作。在接下来的三年里， 我完全期望我的背景和我目前的培训计划能使我成功地 执行拟议的项目。我将接受的指导和培训将使我能够成功过渡 一个独立的研究生涯，可以解决的问题，对根本性的进步， 粘膜免疫，以及用于调查微生物群敏感性疾病的创新和有针对性的策略。

Project Summary Despite a clear link between intestinal immunity and the microbiota, the mechanisms regulating host immune responses to commensal microbes remain poorly understood. Intestinal epithelial cells (IECs) reside at the direct interface between the microbiota and dynamic immune cells and are thus uniquely poised to calibrate host immunity. Although IECs are likely critical for deciphering harmful versus harmless antigens and instructing the appropriate immune reaction, remarkably little is known about mechanisms that enable IECs to modulate host- microbiota interactions. Antigen presenting cells (APCs) must differentiate between harmless and harmful antigens and coordinate proper T cell responses. Although atypical APCs, my preliminary data demonstrate that IECs are the most abundant MHCII-expressing cells in the intestine and that MHCII expression in IECs is directly upregulated by microbiota. Thus, I hypothesize that epithelial antigen presentation may be essential for mediating host-microbiota interactions that impact intestinal homeostasis and inflammation. Studies outlined in this proposal will directly test this hypothesis by defining the function of IEC-intrinsic MHCII. Employing newly developed mutant mouse strains, intestinal organoids, and established models of intestinal inflammation, two specific aims are proposed that will determine (i) the influence of IEC-intrinsic MHCII expression on mucosal barrier function and immune homeostasis and (ii) how IEC-intrinsic MHCII regulates development of intestinal inflammation. Collectively, these studies will provide new insights into how microbiota direct intestinal immunity and will guide novel approaches for investigating and treating intestinal inflammatory diseases. During my past research experiences, I discovered my strong interest in the host-microbiota relationship. For this reason, I initiated the proposed project with Dr. Theresa Alenghat that will build upon my knowledge of innate immunity and antigen presentation and enable me to transition into the field of mucosal immunology. My thesis work provided me with an excellent foundation in host-pathogen interactions, microbiology, and immunology, but I have not had previous exposure to epithelial regulation, antigen-specific techniques, and intestinal disease models. The labs of my mentors, Dr. Alenghat and Dr. Sing Sing Way, along with the exceptional scientific and intellectual environment at Cincinnati Children’s Hospital will enable me to utilize modern, innovative approaches in my research and collaborate with top investigators. Over the next three years, I fully anticipate that my background in conjunction with my current training plan will allow me to successfully carry out the proposed project. The mentoring and training I will receive will enable me to successfully transition to an independent research career that can address questions directed towards fundamental advances in mucosal immunity, as well as innovative and targeted strategies for investigating microbiota-sensitive diseases.