The antigen-dependent activation and inactivation of CD4 T cells

免疫系统会对外来入侵者做出反应，但对“自身”细胞或分子却没有反应。免疫系统的这一特性被称为自我非自我歧视。有两种公认的机制，通过这种机制，对自身抗原的反应能力被削弱。首先，在支持淋巴细胞发育的器官中，具有与自身抗原结合的受体的淋巴细胞在与抗原相互作用时被吞噬。一些“外周”自身抗原在这些器官中存在不足，无法吞噬相应的淋巴细胞。因此，成熟淋巴细胞池，通过血液循环，通过脾脏和淋巴结，包含一些淋巴细胞特异性的这些外周自身抗原。这些淋巴细胞的不适当激活可导致自身免疫。成熟淋巴细胞可以灭活（消融的第二种机制）或被抗原激活，后一种过程导致介导免疫反应的细胞，例如产生抗体的细胞。淋巴细胞有三种。B细胞的活化产生产生抗体的细胞；CD8 T淋巴细胞转化为细胞毒性T淋巴细胞（CTL）， CTL能够杀死病毒感染的细胞或癌细胞；和CD4 T淋巴细胞转化为辅助性T细胞，辅助性T细胞允许抗原促进或帮助激活B细胞和CD8细胞。我们在1970年提出，与抗原相互作用的单个淋巴细胞会被灭活，而靶淋巴细胞的激活需要抗原介导的与抗原特异性Th细胞的相互作用，这提供了一种机制，通过这种机制可以消融外周自身抗原特异性淋巴细胞，激活外源抗原特异性淋巴细胞。随后的研究结果支持了这一观点，即抗原激活B细胞和CD8 T细胞需要Th细胞，而在没有Th细胞的情况下，抗原会使B细胞和CD8 T细胞失活。提出的研究将测试一个详细的假设，即抗原如何与CD4 T细胞相互作用以激活或灭活它们。该假说认为，单个靶CD4 T细胞会被抗原灭活，而其激活需要另一个CD4 T细胞的帮助，即需要CD4 T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，观察结果更能支持这一观点，而且在生理学上也更可信。此外，所有人都同意导致CD4 T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，以设想如何对外周自身抗原产生自身免疫，以及如何通过增加CD4 T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.