Alternative MHCII Processing of Influenza Virus Proteins

描述(由申请人提供)：在包括流感在内的几种人类感染中，CD4+T细胞(TCD4+)的充分参与对取得积极结果至关重要。TCD4+被病原体衍生的多肽(表位)和主要组织相容性II类分子(MHCII)的复合体激活，这些复合体在承载抗原的细胞内产生，然后被运输到细胞表面，在那里它们可以被T细胞受体结合。根据惯例，多肽-MHCII复合体是在细胞外(“外源”)抗原内化、内细胞室内蛋白分解并加载到新生的MHCII体内后形成的。这一经典途径主要是通过对耐久球状蛋白的研究而推导出来的。当病毒被利用时，额外的抗原处理方案变得明显。更重要的是，我们最近的研究表明，这些替代方案并非无关紧要。事实上，在C57BL/6(B6)小鼠模型中，它们主要通过内源性途径驱动大部分抗流感TCD4+反应。因此，替代的MHCII抗原处理值得比目前接受的更多的关注。这项工作被组织成三个独立但高度集成的特定目标，这里提出的工作将：1)调查不同途径处理表位的机制基础，2)探索不仅非常规抗原处理，而且非传统抗原提呈细胞(APC)驱动对流感肺部感染的反应的可能性，以及3)确定用于产生表位的处理途径是否是TCD4+扩增和功能从而保护能力的主要决定因素。这些研究是我们扩大MHCII抗原处理范围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，他们可能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。

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.