The antigen-dependent activation and inactivation of CD4 T cells

CD4 T 细胞的抗原依赖性激活和失活

• 批准号: RGPIN-2018-04117
• 负责人: Bretscher, Peter
• 金额: $ 7.29万
• 依托单位: University of Saskatchewan
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=761018
• 关键词: antigen; dependent; activation; inactivation; CD4

Immune systems respond to fight foreign invaders and yet do not respond to "self" cells or molecules. This attribute of the immune system is referred to as self-nonself discrimination. There are two recognized mechanisms by which the ability to respond against self antigens is ablated. Firstly, lymphocytes with receptors that bind to self-antigens are ablated on interacting with the antigen when first generated in the organs supporting lymphocyte development. Some "peripheral" self-antigens are insufficiently present in such organs to ablate their corresponding lymphocytes. Thus the pool of mature lymphocytes, that circulates via the blood and traffics through the spleen and lymph nodes, contains some lymphocytes specific for these peripheral self antigens. The inappropriate activation of these lymphocytes can result in autoimmunity. Mature lymphocytes can be inactivated (the second mechanism of ablation) or activated by antigen, the latter process resulting in the cells that mediate immune responses, for example antibody producing cells. There are three classes of lymphocytes. The activation of B cells gives rise to cells that produce antibody; of "CD8 T lymphocytes" to cytotoxic T lymphocytes (CTL) that kill virally-infected or cancer cells; and of CD4 T lymphocytes to T helper (Th) cells that allow antigen to facilitate or help in the activation of B and CD8 cells. We proposed in 1970 that a single lymphocyte interacting with antigen would be inactivated, whereas the activation of a target lymphocyte required its antigen-mediated interaction with antigen-specific Th cells, providing a mechanism by which lymphocytes specific for peripheral self-antigens could be ablated and lymphocytes specific for foreign antigens activated. This idea was supported by the subsequent findings that Th cells are required for antigen to activate B and CD8 T cells, and their inactivation by antigen in the absence of Th cells. The studies proposed will test a detailed hypothesis for how antigen interacts differently with CD4 T cells to activate or inactivate them. This hypothesis incorporates the idea that a single target CD4 T will be inactivated by antigen, whereas its activation requires help from another CD4 T cell, i.e. requires CD4 T cell cooperation. Our hypothesis is contrary to the ideas most immunologists currently hold. We argue it is both better supported by observation and is physiologically more plausible. Moreover, all agree that the different circumstances leading to the antigen-dependent activation or inactivation of CD4 T cells is a most critical question, as it appears that such activation is required to initiate almost all adaptive immune responses. Thus an understanding of these circumstances is required to envisage how autoimmunity to peripheral self antigens can occur and how the strength of immune responses can be facilitated by increasing the effective activation of CD4 T cells.

免疫系统会对外来入侵者做出反应，但不会对“自我”细胞或分子做出反应。免疫系统的这种属性被称为自我-非自我辨别。有两种公认的机制可以消除对自身抗原的反应能力。首先，具有与自身抗原结合的受体的淋巴细胞在支持淋巴细胞发育的器官中首次产生时在与抗原相互作用时被消融。一些“外周”自身抗原在这些器官中不足以消融它们相应的淋巴细胞。因此，通过血液循环并通过脾脏和淋巴结运输的成熟淋巴细胞库包含一些对这些外周自身抗原特异性的淋巴细胞。这些淋巴细胞的不适当活化可导致自身免疫。成熟的淋巴细胞可以被抗原灭活（第二种消融机制）或激活，后一种过程产生介导免疫应答的细胞，例如抗体产生细胞。 淋巴细胞有三类。B细胞的活化产生产生抗体的细胞;“CD 8 T淋巴细胞”产生杀死病毒感染细胞或癌细胞的细胞毒性T淋巴细胞（CTL）;以及CD 4 T淋巴细胞产生T辅助（Th）细胞，其允许抗原促进或帮助B和CD 8细胞的活化。我们在1970年提出，与抗原相互作用的单个淋巴细胞将被灭活，而靶淋巴细胞的激活需要其与抗原特异性Th细胞的抗原介导的相互作用，提供了一种机制，通过这种机制，对外周自身抗原特异性的淋巴细胞可以被消融，对外来抗原特异性的淋巴细胞被激活。随后的发现支持了这一想法，即Th细胞是抗原激活B和CD 8 T细胞所必需的，并且在Th细胞不存在的情况下抗原使它们失活。这些研究将测试一个详细的假设，即抗原如何与CD 4 T细胞发生不同的相互作用，以激活或抑制它们。该假设结合了单个靶CD 4 T将被抗原灭活的想法，而其活化需要另一个CD 4 T细胞的帮助，即需要CD 4 T细胞合作。我们的假设与大多数免疫学家目前持有的观点相反。我们认为，这是更好地支持观察和生理上更合理。此外，所有人都同意，导致CD 4 T细胞抗原依赖性活化或失活的不同情况是一个最关键的问题，因为似乎这种活化是启动几乎所有适应性免疫应答所必需的。因此，需要了解这些情况，以设想如何发生对外周自身抗原的自身免疫，以及如何通过增加CD 4 T细胞的有效活化来促进免疫应答的强度。