Epithelial antigen presentation in regulation of the host-microbiota relationship

项目摘要 尽管肠道免疫和微生物区系之间存在明显的联系，但调节宿主免疫的机制 对共生微生物的反应仍然知之甚少。肠上皮细胞(IECS)直接位于 微生物区系和动态免疫细胞之间的接口，因此能够唯一地校准宿主 豁免权。尽管IEC对于破译有害和无害的抗原以及指导 适当的免疫反应，人们对IECS调节宿主的机制知之甚少。 微生物区系相互作用。抗原提呈细胞(APC)必须区分无害和有害 抗原和协调适当的T细胞反应。尽管不是典型的APC，但我的初步数据表明 IECs是肠道中表达MHCII最丰富的细胞，IECs中MHCII的表达直接 被微生物区系上调。因此，我推测上皮抗原递呈可能是 调节宿主-微生物区系的相互作用，从而影响肠道内环境的稳定和炎症。中概述的研究 这一提议将通过定义IEC固有的MHCII功能来直接检验这一假说。新聘员工 开发了突变的小鼠品系，肠道器官，并建立了肠道炎症模型，两个 提出了确定(I)IEC内源性MHCII表达对粘膜的影响的具体目标 屏障功能与免疫动态平衡及(II)IEC内源性MHCII如何调节肠道发育 发炎。总的来说，这些研究将为微生物区系如何引导肠道免疫提供新的见解。 并将指导研究和治疗肠道炎症性疾病的新方法。 在我过去的研究经验中，我发现我对宿主-微生物区系之间的关系非常感兴趣。 出于这个原因，我与Theresa Alenghat博士一起发起了拟议的项目，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。我的 论文工作为我在宿主-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，和 肠道疾病模型。我的导师Alenghat博士和Sing Sing Way博士的实验室以及 辛辛那提儿童医院独特的科学和智力环境将使我能够利用 在我的研究中采用现代的创新方法，并与顶级调查人员合作。在接下来的三年里， 我完全相信，我的背景加上我目前的培训计划将使我能够成功 执行拟议的项目。我将得到的指导和培训将使我能够成功过渡 独立的研究生涯，可以解决与根本性进展有关的问题 粘膜免疫，以及研究微生物区系敏感疾病的创新和有针对性的战略。

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.