Toll-like Receptor Control of MHC Class I Endocytosis

MHC I 类内吞作用的 Toll 样受体控制

基本信息

批准号：
10453097
负责人：
Julie Magarian Blander
金额：
$ 25.43万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10453097
关键词：
ADP-ribosylation factor 6 Adjuvanticity Amino Acids Antigen Presentation Antigen Presentation Pathway Antigens Bacteria Binding Biology Bone Marrow CD14 Antigen CD14 gene CD8-Positive T-Lymphocytes CD8B1 gene Cell Therapy Cell membrane Cell physiology Cell surface Cells Characteristics Classification Clathrin Clinical Communicable Diseases Couples Coupling Cross Presentation Dendritic Cells Dengue Dissection Ebola Endocytosis Event Future Genes Genetic Transcription Genetically Engineered Mouse HIV Heterogeneity Histocompatibility Antigens Class I Homeostasis Human ITAM Immune signaling Immunity In Vitro Infection Inflammation Inflammatory Influenza Knowledge Licensing Link MHC Class I Genes Major Histocompatibility Complex Malignant Neoplasms Mediating Mediator of activation protein Mus Names Nature Peptides Peripheral Phagocytosis Phosphatidylinositol 4,5-Diphosphate Phosphatidylinositols Phosphorylation Plasma Process Protein Engineering Proteins Receptor Signaling Recycling Regulation Reporting Role Seminal Signal Transduction Site Source T cell response T-Lymphocyte TLR1 gene TLR2 gene TLR3 gene TLR4 gene TYROBP gene Therapeutic Tissues Toll-like receptors Transcript Translating Tyrosine Vaccine Design Vaccines Viral Virus Virus Diseases Work base betacoronavirus cell type comparative cytotoxic cytotoxic CD8 T cells design extracellular high dimensionality insight lymphoid organ medical specialties microorganism monocyte new therapeutic target novel pandemic disease pathogen programs receptor tool trafficking transcriptomics tumor

项目摘要

PROPOSAL SUMMARY Cross-presentation is the process whereby major histocompatibility complex class I (MHC-I) molecules are loaded with peptides derived from an extracellular source of proteins including internalized soluble proteins, microorganisms and dying cells. Cross-presentation is a specialty of dendritic cells (DCs), cell types responsible for priming naïve T cells, but even in DCs, this specialty can come naturally or must be acquired upon activation. Conventional DCs known as cDC1 are potent cross-presenters and can do so constitutively, while inflammatory monocyte-derived DCs found in inflamed tissues and another subset of conventional DCs, cDC2, can also cross- present under conditions of infection and inflammation. Parallel to the well-established heterogeneity of DCs in tissues at steady state and inflammation, DC subsets have different functional states during homeostasis or inflammation. This functional difference is primarily orchestrated by the engagement of innate signaling receptors, such as Toll-like receptors (TLRs), that mediate diverse cellular programs including the transcription of inflammatory genes and mediators, as well as the rapid reorganization of subcellular vesicular traffic through post-translational events such as phosphorylation. It is imperative that we investigate the full spectrum of DC functions under inflammation when innate receptors are engaged, and to not be limited to DC classifications as subsets with rigid inflexible functions. Defining the nature of the inflammatory innate receptors and signals that enable DCs to augment their cross-presentation capacity or to acquire it anew, will inform vaccine design for infectious diseases and cancer where cytotoxic CD8 T cells are absolutely essential for organismal survival. A mechanistic dissection of the regulation of cross-presentation is important for the identification of novel therapeutic targets that can be exploited to harness CD8 T cell immunity and confer long term protection against future infection or cancer resurgence. Antigen internalization, processing, and presentation rely heavily on subcellular vesicular traffic. In vitro tools developed for studying murine conventional DCs have served as the workhorse responsible for seminal discoveries of the mechanisms of cross-presentation and its regulation, which have translated to human DC subsets and have impacted vaccine design and cellular therapies. Such tools have enabled our discovery of endosomal recycling compartment stores of MHC-I critical for cross-presentation and depleted upon infection by immunoevasive viruses, findings that have been replicated in human DCs. We have now discovered a new link between cross-presentation of endocytosed antigen and a particular innate receptor reported to be expressed by cultured DCs, inflammatory DCs and a cDC2 subset. We hypothesize this receptor intersects MHC-I traffic with endocytic antigen to license cross-presentation during infection. Using cultured and ex-vivo DCs isolated from the lymphoid organs of mice, we will define the distinct innate immune signaling components that regulate MHC-I endocytosis. We will determine the features of MHC-I that enable its regulated endocytosis. Our studies will inform urgently needed T cell vaccines against infectious diseases and cancer.

提案摘要交叉呈递是主要组织相容性复合物 I 类 (MHC-I) 分子被装载有来自细胞外蛋白质来源的肽，包括内化的可溶性蛋白质，微生物和垂死细胞的交叉呈递是树突状细胞 (DC) 的特长，这是负责的细胞类型。用于启动幼稚 T 细胞，但即使在 DC 中，这种特性也可以自然产生或必须在激活后获得。称为 cDC1 的传统 DC 是有效的交叉呈递者，并且可以组成型地进行交叉呈递，而炎症在发炎组织中发现的单核细胞衍生的 DC 和传统 DC 的另一个子集 cDC2 也可以交叉与感染和炎症条件下 DC 的异质性相似。在稳态和炎症状态下的组织中，DC亚群在稳态或炎症期间具有不同的功能状态这种功能差异主要是通过先天信号受体的参与来协调的。例如 Toll 样受体 (TLR)，介导多种细胞程序，包括转录炎症基因和介质，以及亚细胞囊泡交通的快速重组我们必须研究 DC 的全谱。当先天受体参与时，在炎症下发挥作用，并且不限于 DC 分类具有严格不灵活功能的子集定义了炎症先天受体和信号的性质。使 DC 能够增强其交叉表达能力或重新获得这种能力，将为疫苗设计提供信息传染病和癌症中，细胞毒性 CD8 T 细胞对于生物生存绝对必要。交叉呈现调节的机制剖析对于识别新颖的治疗靶点可用于利用 CD8 T 细胞免疫并提供长期保护未来的感染或癌症复发很大程度上依赖于抗原的内化、加工和呈现。为研究小鼠传统树突状细胞而开发的体外工具已成为亚细胞囊泡交通的研究工具。负责交叉呈现机制及其调节的开创性发现的主力，已转化为人类 DC 子集并影响了疫苗设计和细胞疗法。使我们能够发现 MHC-I 的内体回收室库，这对于交叉呈递和被免疫逃避病毒感染后就会耗尽，这一发现已在人类树突状细胞中得到复制。现在发现了内吞抗原交叉呈递与特定先天受体之间的新联系据报道由培养的 DC、炎症 DC 和 cDC2 子集表达。使用培养和内吞抗原将 MHC-I 运输相交叉以允许交叉呈递。从小鼠淋巴器官中分离出离体 DC，我们将定义独特的先天免疫信号调节 MHC-I 内吞作用的成分我们将确定 MHC-I 的特征，使其能够受到调节。我们的研究将为迫切需要的针对传染病和癌症的 T 细胞疫苗提供信息。