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.

提案摘要交叉表现是主要的组织相容性复合物I类（MHC-I）分子的过程装有源自蛋白质外源的胡椒体，包括内部固体蛋白，微生物和垂死的细胞。交叉呈递是树突状细胞（DC）的特色菜，电池类型负责对于启动幼稚的T细胞，但即使在DC中，该专业也可以自然或在激活后获得。常规的DC被称为CDC1是潜在的交叉总统，可以组成型，而炎症则可以做到这一点在发炎的组织中发现的单核细胞衍生的DC和常规DC的另一个子集Cdc2也可以交叉在感染和注射条件下存在。与DC的公认的异质性平行在稳态和注射处的组织，直流子集在体内稳态或炎。这种功能差异主要是由先天信号接收器的参与来精心策划的例如Toll样受体（TLR），介导了各种细胞程序，包括转录炎症基因和介体，以及亚细胞流量通过翻译后事件，例如磷酸化。我们必须研究DC的完整范围当与先天受体参与时，在炎症下的功能，而不仅限于DC分类为具有刚性不足功能的子集。定义炎症先天受体和信号的性质使DC能够增强其交叉呈递能力或重新获得它，将为疫苗设计提供信息传染病和癌症，其中细胞毒性CD8 T细胞对于有机生存绝对必要。一个交叉呈递调节的机械解剖对于鉴定新颖可以探索的治疗靶标CD8 T细胞免疫和会议长期保护未来感染或癌症复兴。抗原内在化，加工和演示很大程度上取决于亚细胞流量。开发用于研究鼠常规DC的体外工具已成为主力负责跨表达机制及其法规的第二次发现，已转化为人类直流子集，并影响了疫苗设计和细胞疗法。这样的工具有使我们发现了MHC-1的内体回收室，对交叉呈递至关重要免疫宣传病毒感染后，已在人类DC中复制的发现耗尽。我们有现在发现了内吞抗原的交叉表现与特定先天接收器之间的新联系据报道，通过培养的DC，炎症DC和CDC2子集表示。我们假设这个接收器与内吞抗原相交的MHC-1流量在感染过程中许可交叉呈现。使用培养和从小鼠的淋巴机器人器官分离出的前体病毒DC，我们将定义不同的先天免疫信号传导调节MHC-I内吞作用的成分。我们将确定MHC-I的特征，以使其受监管内吞作用。我们的研究将为急需T细胞疫苗提供针对感染疾病和癌症的疫苗。