Mechanisms of Effector CD4 Cell Tolerization

描述(申请人提供)：免疫系统已经进化为中和病原体，然而，它也必须致力于避免破坏其工作是防御的组织。就T淋巴细胞而言，大多数潜在的自我反应细胞在胸腺发育过程中被删除。然而，识别胸腺中没有出现的自身抗原的T细胞将经历成熟，并且必须在外周变得耐受(即，不起作用)。一般来说，由于炎症(即危险)信号的存在，抗原缺乏经验(即幼稚)的T细胞在遇到同源病原体衍生的抗原时，会准备好表达效应器/记忆功能。相反，当它们的同源抗原来自自身时，缺乏炎症会导致耐受诱导信号。有趣的是，当T细胞遇到在免疫原性和耐受性环境中表达的同源抗原时，可能存在生理情况。因此，如果最近的胸腺移植物是自身特有的，但最初受到表达交叉反应表位(即分子模仿)的病原体的刺激，他们可能会发展出效应器功能，并有可能导致自身免疫病理。如果这些效应性T细胞对耐受性很敏感，那么随之而来的自身免疫损伤的程度可能会降到最低。此外，效应性T细胞的耐受性也可能对基于T细胞的癌症治疗产生负面影响，因为肿瘤抗原可以以耐受性的方式呈现。我们最近发现，病毒诱导的CD4细胞在遇到表达为实质自身抗原(即使在低水平表达时)的同源抗原时，可以通过诱导原始CD4细胞耐受的相同间接抗原提呈途径被诱导耐受。有趣的是，在这种耐受过程中，病毒诱导的CD4细胞表达效应性细胞因子如肿瘤坏死因子-α和干扰素--的能力比表达非效应性功能如IL-2的产生和增殖的能力丧失得更快。此外，耐受主要通过功能失活(而不是缺失)来调节，并在淋巴和非淋巴器官中都表现出来。这项建议将研究控制这一新的外周耐受途径的细胞和分子机制。

DESCRIPTION (provided by applicant): The immune system has evolved to neutralize pathogens, however, it must also dedicate much of its energy towards the avoidance of damaging the tissues whose job it is to defend. In the case of T lymphocytes, most potentially self-reactive cells are deleted during thymic development. T cells that recognize self-antigens not presented in the thymus will undergo maturation, however, and must be rendered tolerant (i.e., non-functional) in the periphery. Generally speaking, antigen-inexperienced (i.e., naive) T cells are primed to express effector/memory functions when they encounter cognate pathogen-derived antigens due to the presence of inflammatory (i.e., danger) signals. In contrast, when their cognate antigens derive from self, the lack of inflammation results in tolerance inducing signals. Interestingly, there might be physiological circumstances when T cells encounter cognate antigens expressed in both immunogenic and tolerogenic contexts. Thus, if recent thymic immigrants are specific to self, but are initially stimulated by a pathogen that expresses a cross-reactive epitope (i.e., molecular mimicry), they would likely develop effector functions and the potential to cause autoimmune pathology. If these effector T cells were susceptible to tolerization, the extent of ensuing autoimmune damage might be minimized. Additionally, the potential of effector T cells to be tolerized might also negatively impact T cell-based therapies to treat cancer since tumor antigens can be presented in a tolerogenic manner. We have recently shown that virally-primed CD4 cells can be induced to undergo tolerization when they encounter their cognate antigen expressed as a parenchymal self-antigen (even when expressed at low levels), via the same indirect antigen presentation pathway that induces na'ive CD4 cell tolerization. Interestingly, during this tolerization process the ability of virally-primed CD4 cells to express effector cytokines such as TNF-a and IFN-_ are lost more rapidly than their ability to express noneffector functions such as IL-2 production and proliferation. Furthermore, tolerization is mediated primarily through functional inactivation (rather than deletion), and is manifested in both lymphoid and non-lymphoid organs. This proposal will examine the cellular and molecular mechanisms that govern the regulation of this novel peripheral tolerization pathway.