Mechanisms of Effector CD4 Cell Tolerization

描述（由申请人提供）：免疫系统已经进化到可以中和病原体，然而，它也必须将其大部分能量用于避免损害其保护的组织。在T淋巴细胞的情况下，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，识别胸腺中未呈现的自身抗原的T细胞将经历成熟，并且必须在周围细胞中表现出耐受性（即无功能）。一般来说，缺乏抗原（即幼稚）的T细胞在遇到同源病原体衍生抗原时，由于炎症（即危险）信号的存在，会启动表达效应/记忆功能。相反，当同源抗原来源于自身时，缺乏炎症导致耐受诱导信号。有趣的是，当T细胞遇到在免疫原和耐受原环境中表达的同源抗原时，可能存在生理环境。因此，如果最近的胸腺移植物是自身特异性的，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，它们可能会产生效应功能，并有可能引起自身免疫病理。如果这些效应T细胞对耐受性敏感，那么随后的自身免疫损伤的程度可能会被最小化。此外，效应T细胞被耐受的潜力也可能对基于T细胞的治疗癌症的疗法产生负面影响，因为肿瘤抗原可以以耐受性的方式呈现。我们最近的研究表明，当病毒引发的CD4细胞遇到以实质自身抗原表达的同源抗原（即使表达水平很低）时，它们可以通过诱导初始CD4细胞耐受的间接抗原呈递途径诱导耐受。有趣的是，在这个耐受过程中，病毒引发的CD4细胞表达效应细胞因子（如TNF-a和IFN-_）的能力比表达非效应功能（如IL-2的产生和增殖）的能力丧失得更快。此外，耐受性主要是通过功能失活（而不是缺失）介导的，并且在淋巴和非淋巴器官中都表现出来。本提案将研究控制这种新型外周耐受途径调控的细胞和分子机制。

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.