Alternative MHCII Processing of Influenza Virus Proteins

流感病毒蛋白的替代 MHCII 加工

基本信息

批准号：
9280869
负责人：
Laurence Crane Eisenlohr
金额：
$ 54.61万
依托单位：
CHILDREN'S HOSP OF PHILADELPHIA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9280869
关键词：
Alpha Cell Antigen-Presenting Cells Antigens Attention Autoimmune Diseases Binding Biological Assay Bone Marrow CD4 Positive T Lymphocytes Catalysis Cell Extracts Cell surface Cells Chimera organism Complex Data Development Engineering Epitopes Equilibrium Flow Cytometry Generations Genetically Engineered Mouse Goals Histocompatibility Histocompatibility Antigens Class II Human Immune response Immunization Immunize Inbred BALB C Mice Individual Infection Infectious Agent Influenza Influenza A virus Investigation Liquid substance Lung Malignant Neoplasms MicroRNAs Mus Nature Outcome Pathway interactions Peptide Hydrolases Peptides Play Predisposition Preparation Process Proteins Proteolysis Research Scheme Specificity T-Cell Receptor Testing Time Vaccine Design Vaccines Viral Proteins Virus Work anti-influenza antigen processing base cancer immunotherapy cancer therapy cell type computerized tools experimental study extracellular flu fluidity globular protein imaging study in vivo influenzavirus insight late endosome lymph nodes mouse model novel strategies novel vaccines pathogen protein expression public health relevance response symposium synthetic peptide

项目摘要

DESCRIPTION (provided by applicant): Sufficient engagement of CD4+ T cells (TCD4+) is critical for a positive outcome in several human infections, including influenza (flu). TCD4+ are activated by complexes of pathogen-derived peptides (epitopes) and major histocompatibility class II molecules (MHCII) that are generated within the antigen bearing cell and then transported to the cell surface where they can be engaged by T cell receptor. According to convention, peptide-MHCII complexes are formed following internalization of extracellular ("exogenous") antigen, proteolysis within the endocytic compartment and loading onto nascent MHCII in a late endosomal compartment. This classical pathway has been deduced mainly through study of durable globular proteins. When viruses are utilized, additional antigen processing schemes become apparent. What is more, our recent work is showing that these alternatives are not inconsequential. Indeed, through mainly endogenous pathways, they drive the bulk of the anti-influenza TCD4+ response in a C57Bl/6 (B6) mouse model. Thus, alternative MHCII antigen processing merits far greater attention than it is currently receiving. Organized into three independent but highly integrated specific aims, the work proposed here will: 1) investigate the mechanistic bases by which epitopes are processed by different pathways, 2) explore the possibility that not just unconventional antigen processing but also unconventional antigen-presenting cells (APCs) drive the response to an influenza lung infection, and 3) determine whether the processing pathway utilized to generate an epitope is a major determinant of TCD4+ expansion and functionality and, hence, protective capacity. These studies, a key component of our larger effort to expand the landscape of MHCII antigen processing, could substantially impact the rational design of vaccines against many pathogens. Further, they could point to new approaches to cancer immunotherapy, and provide important insight into the genesis and treatment of autoimmune diseases.

描述（由申请人提供）：CD4+ T 细胞 (TCD4+) 的充分参与对于多种人类感染（包括流感）的积极结果至关重要。 TCD4+ 被病原体衍生肽（表位）和主要组织相容性 II 类分子 (MHCII) 的复合物激活，这些复合物在承载抗原的细胞内产生，然后转运到细胞表面，在那里它们可以被 T 细胞受体结合。根据惯例，肽-MHCII复合物是在细胞外（“外源”）抗原内化、内吞区室中的蛋白水解并加载到晚期内体区室中的新生MHCII上之后形成的。这一经典途径主要是通过对持久球状蛋白的研究而推导出来的。当利用病毒时，额外的抗原处理方案变得显而易见。更重要的是，我们最近的工作表明这些替代方案并非无关紧要。事实上，它们主要通过内源性途径，在 C57Bl/6 (B6) 小鼠模型中驱动大部分抗流感 TCD4+ 反应。因此，替代性 MHCII 抗原处理比目前受到的关注更值得关注。这里提出的工作分为三个独立但高度整合的具体目标，将：1）研究表位通过不同途径加工的机制基础，2）探索不仅非常规抗原加工而且非常规抗原呈递细胞的可能性（ APC) 驱动对流感肺部感染的反应，3) 确定用于生成表位的处理途径是否是 TCD4+ 扩展和功能以及保护能力的主要决定因素。这些研究是我们扩大 MHCII 抗原加工领域的更大努力的关键组成部分，可能会对针对许多病原体的疫苗的合理设计产生重大影响。此外，他们还可以指出癌症免疫治疗的新方法，并为自身免疫性疾病的发生和治疗提供重要的见解。