Alternative MHCII Processing of Influenza Virus Proteins

描述（由申请方提供）：充分参与CD 4 + T细胞（TCD 4+）对于几种人类感染（包括流感）的阳性结果至关重要。TCD 4+被病原体衍生的肽（表位）和主要组织相容性II类分子（MHCII）的复合物激活，所述复合物在携带抗原的细胞内产生，然后转运到细胞表面，在那里它们可以被T细胞受体接合。根据惯例，肽-MHCII复合物在细胞外（“外源性”）抗原内化、内吞区室内的蛋白水解和加载到晚期内体区室中的新生MHCII上之后形成。这一经典途径主要是通过对持久性球状蛋白的研究推导出来的。当使用病毒时，另外的抗原加工方案变得明显。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驱动C57 B1/6（B6）小鼠模型中的大部分抗流感T ⑶ 4+应答。因此，替代MHCII抗原处理值得比目前更大的关注。这里提出的工作分为三个独立但高度综合的具体目标，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（APC）驱动对流感肺部感染的应答的可能性，和3）确定用于产生表位的加工途径是否是TCD 4+扩增和功能性的主要决定因素，并因此确定保护能力。这些研究是我们扩大MHCII抗原加工领域的重要组成部分，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。

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.