Alternative Pathways for CD4+ T Cell Epitope Generation from Influenza Antigens

描述(由申请人提供)：在包括流感(流感)在内的几种人类感染中，CD4T细胞(TCD4)的充分参与对取得积极结果至关重要。TCD4是由病原体衍生的多肽(表位)和主要组织相容性II类分子(MHCII)的复合体激活的，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复合体是在外源抗原内化、内细胞室内蛋白分解和装载到新生的MHCII上后形成的。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。当使用感染剂时，额外的多肽生成途径(“抗原加工”)变得明显，有些途径始于内源性抗原来源(在呈递细胞内合成)。我们已经开始解决的一个关键问题是，这些替代途径在多大程度上推动了TCD4对真正病原体的总反应。使用流感感染的C57BL/6(B6)模型，初步结果表明，在解释TCD4反应的14个表位中，有惊人的13个可以非经典地产生。因此，这一研究路线可能会极大地修改基本免疫学的基本原则。这项工作分为四个独立但高度整合的特定目标，将在这些发现的基础上进行巩固和扩展，调查不同的“专业”APC(树突状细胞、巨噬细胞和B细胞)在原发和继发反应中替代处理流感蛋白的相对能力，并确定用于产生表位的处理途径是否会影响TCD4功能水平，从而影响保护能力。这些研究的结果可能会对针对一系列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。

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 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 infectious agents are used, additional pathways of peptide generation ("antigen processing") become apparent, some that begin with endogenous sources of antigen (synthesized within the presenting cell). A critical question that we have begun to address is the extent to which these alternative pathways drive the total TCD4+ response to a bona fide pathogen. Using a C57Bl/6 (B6) model of influenza infection, preliminary results indicate that an astonishing 13 of the 14 epitopes that account for the TCD4+ response can be generated non-classically. Thus, this line of investigation could dramatically revise a fundamental principle of basic immunology. Organized in four independent but highly integrated specific aims, the work proposed here will solidify and expand upon these findings, investigate the relative capacities of the different "professional" APCs (dendritic cells, macrophages and B cells) for alternative processing of flu proteins during primary and secondary responses, and determine whether the processing pathway utilized to generate an epitope can impact the level of TCD4+ functionality and, hence, protective capacity. The results of these studies could considerably impact the rational design of vaccines against an array of pathogens. In addition, they could point to new approaches to cancer immunotherapy, and provide important insight into the genesis and treatment of autoimmune diseases.