Alternative MHCII Processing of Influenza Virus Proteins

描述（由申请人提供）：CD4+ T细胞（TCD4+）的充分接触对于包括流感（流感）在内的几种人类感染的阳性结果至关重要。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，这些分子在抗原承载细胞内产生，然后被运输到细胞表面，在那里它们可以被T细胞受体接合。根据惯例，肽-MHCII复合物是在细胞外（“外源”）抗原内化、内噬室内的蛋白水解和后期内体室中装载到新生的MHCII上形成的。这一经典途径主要是通过对持久的球状蛋白的研究推断出来的。当使用病毒时，额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，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MHCII抗原加工值得比目前得到更多的关注。这里提出的工作将分为三个独立但高度综合的具体目标：1)研究表位通过不同途径加工的机制基础，2)探索非常规抗原加工和非常规抗原呈递细胞（APCs）驱动流感肺部感染反应的可能性，以及3)确定用于产生表位的加工途径是否是TCD4+扩增和功能的主要决定因素，从而确定保护能力。这些研究是我们扩大MHCII抗原加工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，它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.