Mechanisms of Effector CD4 Cell Tolerization

效应 CD4 细胞耐受的机制

• 批准号: 7236641
• 负责人: ADAM J ADLER
• 金额: $ 30.93万
• 依托单位: UNIVERSITY OF CONNECTICUT SCH OF MED/DNT
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236641
• 关键词: Mechanisms; Effector; CD4; Cell; Tolerization

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.

描述（由申请人提供）：免疫系统已经进化到可以中和病原体，但是，它还必须将大量能量用于避免损坏其所负责保护的组织。就 T 淋巴细胞而言，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，识别胸腺中未存在的自身抗原的 T 细胞将经历成熟，并且必须在外周表现出耐受性（即无功能）。一般来说，由于炎症（即危险）信号的存在，未经历过抗原（即初始）的 T 细胞在遇到同源病原体衍生抗原时，会准备好表达效应/记忆功能。相反，当它们的同源抗原源自自身时，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背景下表达的同源抗原时，可能存在生理情况。因此，如果最近的胸腺移民对自身具有特异性，但最初受到表达交叉反应表位（即分子拟态）的病原体刺激，它们可能会发展出效应器功能并有可能引起自身免疫病理。如果这些效应T细胞易于耐受，那么随之而来的自身免疫损伤的程度可能会最小化。此外，效应T细胞被耐受的潜力也可能对基于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方式呈递。我们最近表明，当病毒引发的 CD4 细胞遇到表达为实质自身抗原（即使表达水平较低）的同源抗原时，可以通过与诱导初始免疫应答相同的间接抗原呈递途径，诱导其进行耐受。 CD4细胞耐受。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（例如TNF-α和IFN-_）的能力比它们表达非效应功能（例如IL-2产生和增殖）的能力丧失得更快。此外，耐受化主要通过功能失活（而不是缺失）介导，并在淋巴和非淋巴器官中表现出来。该提案将研究控制这种新型外周耐受途径调节的细胞和分子机制。