Regulation and function of nonlymphoid organ CD103+ dendritic cells

项目摘要/摘要 树突状细胞(DC)包括关键抗原(Ag)递呈的免疫细胞，它们对调节 获得性免疫、免疫耐受、免疫记忆和先天反应。第一类常规 DC(CDC1)亚群高度精通主要组织相容性复合体I类抗原的交叉提呈 (MHC-I)和诱导细胞外抗原特异性CD8+T淋巴细胞。因此，已经做出了重大努力 已被应用于了解CDC1s在抗肿瘤免疫中的作用。相比之下，主要差距在于 关于cDC1在胃肠道等周围组织中的功能的知识中心。在第一个 在该奖项的项目期间，我们发现了细胞因子激活信号的关键免疫调节功能 转导和转录激活因子3(STAT3)在cDC1s中。我们的工作还揭示了一个保护角色 CD11c+细胞中的STAT3，包括包括cDC1s在内的多个抗原提呈亚群。我们展示了STAT3- CD11c+细胞缺陷与抗细胞毒T淋巴细胞激活治疗性T细胞协同作用 相关蛋白4(CTLA-4)被阻断，以推动严重的肠道炎症和组织破坏。 此外，我们发现CD11c+细胞中的STAT3缺乏影响了CD11c+细胞的组成和复杂性。 肠道微生物群。使用一种新的模型来删除cDC1s中的STAT3，我们最近发现了STAT3抑制 CDC1介导的胃肠道炎症。综上所述，我们的结果表明cDC1控制肠道炎症。 通过STAT3的内在机制响应和调节与宿主微生物组的关键相互作用，但主要 关于cDc1对肠道免疫和炎症的贡献，或者这是如何实现的，知识中心存在空白 种群受共生微生物区系的调节或影响。为了解决这些差距，我们将测试 CDC1s引导肠道免疫反应以维持体内平衡的中心假说；过度激活 由于失去STAT3而导致的CDC1s在稳态或免疫挑战时加剧了肠道炎症。 激活刺激(例如，、CTLA-4、感染)并破坏共生微生物区系。这一假设将是 研究的三个目的：1)描述cDC1s和cDc1固有的STAT3在结肠炎和 对CTLA-4治疗的反应；2)确定CDC1型和CDC1型固有STAT3缺乏症的后果 在结肠中T细胞生成和T细胞活性；以及3)评估cDC1s和cDc1- 内源性STAT3与肠道微生物群和控制胃肠道病原体驱动的炎症。完成这项工作 该项目将揭示目前未知的肠道免疫的关键方面，包括 CDC1s对肠道免疫的影响以及cDc1固有的STAT3在这些反应中的作用。我们的研究将提供 对cDC1生物学的新的基本见解，并可能有助于确定减轻肠道炎症的方法 与CTLA-4免疫检查点阻断相关的疾病或免疫相关不良事件(IrAE)。

PROJECT SUMMARY/ABSTRACT Dendritic cells (DCs) comprise critical antigen (Ag) presenting immune cells, which are important for regulating adaptive immunity, immune tolerance, immunological memory, and innate responses. The type 1 conventional DC (cDC1) subset is highly proficient in Ag cross-presentation on major histocompatibility complex class I (MHC-I) and induction of CD8+ T lymphocytes specific for extracellular Ag. Accordingly, significant effort has been applied toward understanding roles for cDC1s in anti-tumor immunity. By contrast, major gaps in knowledge center on cDC1 function in peripheral tissues such as the gastrointestinal (GI) tract. In the first project period of this award, we discovered key immune-regulatory functions for the cytokine-activated signal transducer and activator of transcription 3 (STAT3) in cDC1s. Our work also revealed a protective role for STAT3 in CD11c+ cells, comprising multiple Ag-presenting subsets including cDC1s. We showed STAT3- deficiency in CD11c+ cells cooperates with therapeutic T cell activation by anti-cytotoxic T-lymphocyte- associated protein 4 (CTLA-4) blockade to drive severe intestinal inflammation and tissue destruction. Furthermore, we found STAT3-deficiency in CD11c+ cells influences the composition and complexity of the intestinal microbiome. Using a novel model to delete STAT3 in cDC1s, we recently showed STAT3 restrains cDC1-mediated GI inflammation. Taken together, our results suggest cDC1s control intestinal inflammatory responses and mediate key interactions with the host microbiome via STAT3-intrinsic mechanisms, yet major gaps in knowledge center on the contribution of cDC1s to intestinal immunity and inflammation, or how this population is modulated by or affects the commensal microbiota. To address these gaps, we will test the central hypothesis that cDC1s direct intestinal immune responses to maintain homeostasis; overactivation of cDC1s by loss of STAT3 potentiates intestinal inflammation in homeostasis or upon challenge with immune- activating stimuli (e.g., CTLA-4, infection) and disrupts the commensal microbiota. This hypothesis will be examined in three aims: 1) Delineate roles for cDC1s and cDC1-intrinsic STAT3 in colon inflammation and response to CTLA-4 therapy; 2) Determine the consequences of cDC1- and cDC1-intrinsic STAT3-deficiency upon T cell generation and T cell activity in the colon; and 3) Evaluate the interaction of cDC1s and cDC1- intrinsic STAT3 with the gut microbiome and control of GI pathogen-driven inflammation. Completion of this project will reveal key facets of intestinal immunity that are currently unknown, including the contribution of cDC1s to intestinal immunity and roles for cDC1-intrinsic STAT3 in these responses. Our studies will provide new basic insights into cDC1 biology and may aid in identifying approaches to mitigate intestinal inflammatory disorders or immune-related adverse events (irAEs) associated with CTLA-4 immune checkpoint blockade.