Mechanisms of Effector CD4 Cell Tolerization

描述（由申请人提供）：免疫系统已经进化到中和病原体，然而，它还必须将其大部分能量用于避免损伤其工作是防御的组织。在T淋巴细胞的情况下，大多数潜在的自身反应细胞在胸腺发育过程中被删除。然而，识别不在胸腺中呈递的自身抗原的T细胞将经历成熟，并且必须被赋予耐受性（即，非功能性的）。一般来说，抗原无经验的（即，幼稚）T细胞在它们遇到同源病原体来源的抗原时由于炎性的存在而被引发以表达效应/记忆功能（即，危险）信号。相反，当它们的同源抗原来源于自身时，炎症的缺乏导致耐受诱导信号。有趣的是，当T细胞遇到在免疫原性和致耐受性背景下表达的同源抗原时，可能存在生理环境。因此，如果最近的胸腺移民对自身是特异性的，但最初是由表达交叉反应性表位的病原体刺激的（即，分子模拟），它们可能会发展效应子功能并可能导致自身免疫病理学。如果这些效应T细胞对耐受敏感，那么随后的自身免疫损伤的程度可能会最小化。此外，效应T细胞被耐受化的潜力也可能对治疗癌症的基于T细胞的疗法产生负面影响，因为肿瘤抗原可以以致耐受性方式呈递。我们最近已经表明，当病毒致敏的CD 4细胞遇到其表达为实质自身抗原的同源抗原（即使在低水平表达时）时，可以通过诱导初始CD 4细胞耐受化的相同间接抗原呈递途径诱导它们经历耐受化。有趣的是，在该耐受化过程中，病毒致敏的CD 4细胞表达效应细胞因子如TNF-α和IFN-α的能力比其表达非效应功能如IL-2产生和增殖的能力更快地丧失。此外，耐受化主要通过功能失活（而不是缺失）介导，并且在淋巴和非淋巴器官中表现出来。该建议将研究这种新的外周耐受化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.