Orchestrating intestinal immunity through microbiota-CX3CR1+ cell interactions

项目摘要 哺乳动物免疫系统的发育和反应是由一种动态的相互作用形成的 宿主免疫系统和体内微生物群之间的联系一系列人类疾病的发展 与微生物群的变化以及肠道免疫反应的改变有关。我们 先前建立的表达CX 3CR 1的单核吞噬细胞（MNP）群体 趋化因子受体在免疫系统对微生物群的反应和调节 肠内稳态在微生物群存在的情况下，CX 3CR 1 + MNP限制炎症免疫反应。 除了促进调节性T细胞外， 对可溶性fed蛋白的反应。相比之下，去除微生物群会促进炎症性T细胞 许多CX 3CR 1 + MNP功能失调引起的反应，包括产生 抗炎细胞因子IL-10和细胞内细菌的清除。CX 3CR 1 + MNP的进一步失调 功能与炎性病症如炎性肠病（IBD）中的病理学相关。我们 因此，假设在正常条件下，微生物群的特定成员激活细胞， CX 3CR 1 + MNP中负责通过抑制炎性T细胞来限制肠道炎症的通路 反应和促进肠粘膜屏障功能。相反，改变的微生物群组成 通常与胃肠道感染或炎性疾病如IBD相关的药物提供了替代治疗方案， CX 3CR 1 + MNP的信号，驱使它们清除病原体并促进肠道炎症。 然后，重建正常的微生物群应该指导CX 3CR 1 + MNP恢复肠道内稳态。到 为了解决CX 3CR 1 + MNP在诱导肠道免疫应答中的体内作用，我们产生了 新的小鼠品系，其中CX 3CR 1 + MNP可以被选择性地耗尽。我们会用这些老鼠 结合离体测定来研究CX 3CR 1 + MNP中的稳态功能的调节， 微生物群作为一个整体，以及通过选择个别成员。在目标1中，我们将确定微生物群 调节CX 3CR 1 + MNP功能以促进调节性T细胞应答并限制炎症。在目标2中， 将确定微生物群的个体成员及其基因产物对CX 3CR 1 + MNP的影响。 诱导抗炎性T细胞应答。在这些研究结束时，我们将确定并 由微生物群调节的特征性细胞途径，其旨在限制炎症以及 负责诱导这些抗炎途径的微生物基因产物。所有这些 研究将提供关键的见解，在肠道抗炎反应的调制， 微生物群，并将有助于确定额外的临床目标，以促进和重建 肠内稳态

Project Summary The development and responsiveness of the mammalian immune system is shaped by a dynamic interaction between the host immune system and the resident microbiota. The development of a host of human diseases is associated with shifts in the microbiota alongside alterations in the intestinal immune responses. We previously established that a population of mononuclear phagocytes (MNPs) expressing the CX3CR1 chemokine receptor play a central role in the immune system's responses to the microbiota and regulation of intestinal homeostasis. In the presence of the microbiota, CX3CR1+ MNPs limit inflammatory immune responses against both pathogenic bacterial infections and the microbiota itself in addition to promoting Treg responses against soluble fed proteins. In contrast, removal of the microbiota promotes inflammatory T cell responses brought about by dysregulation in a number of CX3CR1+ MNP functions, including production of the anti-inflammatory cytokine IL-10 and clearance of intracellular bacteria. Further dysregulation of CX3CR1+ MNP function is associated with pathology in inflammatory conditions such as inflammatory bowel disease (IBD). We therefore hypothesize that under normal conditions, specific members of the microbiota activate cellular pathways in CX3CR1+ MNPs responsible for limiting intestinal inflammation by restraining inflammatory T cell responses and promoting intestinal mucosal barrier function. Conversely, the shifted microbiota composition frequently associated with gastrointestinal infection or inflammatory disorders such as IBD provide alternative signals to CX3CR1+ MNPs, driving them to pathogen clearance and promoting intestinal inflammation. Reestablishing the normal microbiota should then direct CX3CR1+ MNPs to restore intestinal homeostasis. To address the in vivo role for CX3CR1+ MNPs in the induction of intestinal immune responses, we generated novel mouse strains in which CX3CR1+ MNPs can be selectively depleted. We will use these mice in conjunction with ex vivo assays to study the regulation of homeostatic functions in CX3CR1+ MNPs by the microbiota as a whole as well as by select individual members. In Aim 1, we will determine how the microbiota modulates CX3CR1+ MNP function to promote regulatory T cell responses and limit inflammation. In Aim 2, we will determine the impact of individual members of the microbiota and their gene products on CX3CR1+ MNP- induced anti-inflammatory T cell responses. At the conclusion of these studies, we will have identified and characterized cellular pathways regulated by the microbiota that are designed to limit inflammation as well as the microbial gene products responsible for the induction of these anti-inflammatory pathways. Together, these studies will provide critical insights into the modulation of anti-inflammatory responses in the intestine by the microbiota and will facilitate the identification of additional clinical targets for promoting and reestablishing intestinal homeostasis.