The antigen-dependent activation and inactivation of CD4 T cells

免疫系统对外来入侵者做出反应，但对“自身”细胞或分子没有反应。免疫系统的这种属性被称为自我-非自我歧视。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烧毁。一些“外周”自身抗原在这些器官中的存在不足，不足以杀死它们相应的淋巴细胞。因此，通过血液循环、通过脾和淋巴结运输的成熟淋巴细胞池，包含一些针对这些外周自身抗原的淋巴细胞。这些淋巴细胞的不适当激活可能导致自身免疫。成熟的淋巴细胞可以被灭活(第二种消融机制)，也可以被抗原激活，后者的过程导致介导免疫反应的细胞，例如产生抗体的细胞。*淋巴细胞分为三类。B细胞的激活产生产生抗体的细胞；“CD8 T淋巴细胞”产生杀死病毒感染或癌细胞的细胞毒性T淋巴细胞(CTL)；以及使抗原促进或帮助激活B细胞和CD8细胞的CD4T淋巴细胞产生T辅助细胞(Th)。我们在1970年提出，单个与抗原相互作用的淋巴细胞将被灭活，而靶淋巴细胞的激活需要抗原介导的与抗原特异的Th细胞的相互作用，从而提供了一种机制，通过这种机制，可以去除外周自身抗原特异的淋巴细胞，激活外来抗原特异的淋巴细胞。随后的发现支持了这一观点，即抗原需要Th细胞来激活B和CD8T细胞，而在没有Th细胞的情况下，抗原需要使它们失活。建议的研究将测试一个详细的假设，即抗原如何与CD4T细胞以不同的方式相互作用，以激活或灭活它们。这一假说包含了这样的想法，即单个靶点CD4T将被抗原灭活，而其激活需要另一个CD4T细胞的帮助，即需要CD4T细胞的合作。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，它既得到了更好的观察支持，在生理上也更可信。此外，所有人都同意，导致CD4T细胞抗原依赖性激活或失活的不同情况是一个最关键的问题，因为似乎这种激活是启动几乎所有适应性免疫反应所必需的。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CD4T细胞的有效激活来促进免疫反应的强度。

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.