Grewal I S, Flavell R A
Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06510, USA.
Immunol Rev. 1996 Oct;153:85-106. doi: 10.1111/j.1600-065x.1996.tb00921.x.
It is clear by now that cell-to-cell interactions involving a variety of signals are required for effective immune response. The data reviewed here suggest that CD40-CD40L interactions are critical for development of CD4 T-cell-dependent effector functions. Lack of this important interaction results in greatly reduced activation of CD4 T cells, while successful interaction of these molecules results in full activation of these T cells. Consequently, the absence of CD40-CD40L interactions leads to impairment of T-cell effector such as help for B-cell differentiation and class switch, activation of monocytes and macrophages to produce cytokines and to kill intracellular pathogens, and activation of autoreactive T cells to mount an autoimmune response. The effector functions of T cells controlled by CD40-CD40L interactions in a successful immune response are given in Table I. Data presented so far suggest that CD40-CD40L interactions play a role in early signalling events, where interactions of this kind are required to induce expression of costimulatory molecules on APC. One possible sequence of events in that APC, like DC, take up antigens at the site of injury or infection and migrate to lymph nodes, where they present antigens complexed with MHC class II molecules to naive T cells. This results in expression of CD40L on T cells. Coupling of this newly expressed CD40L on T cells with CD40 on APC results in expression of the costimulatory activity of the APC. At this time the costimulatory signal provided by the APC is received by the T cells via CD28/CTLA-4, which drives the cell to enter into cell cycle and complete T cell activation. T cells thereby activated can now enter into secondary cognate CD40-CD40L-dependent effector recognition with B cells to switch Ig class, macrophages to produce cytokines and new DC carrying the same antigen to up-regulate costimulatory activity. A tight regulation of expression of CD40L on T cells and costimulatory activity on APC would prevent activation of unwanted bystander T cells. The coupling of activation of the APC primed with the cognate antigen to the activation of the T-cell specific for that antigen in this model provides an additional regulatory step in the initiation of the immune response. This also suggests that a limited number of T cells/APC will be activated, both of which will be specific in nature. This additional step may be important for safeguarding against an autoimmune response. In addition, the fact that CD40L uniquely seems to play this role suggests that selective immunotherapies to treat autoimmune disease and prevent graft rejection can be targeted on this molecule. On the other hand, CD40-directed approaches to up-regulate costimulatory activity on APC could be developed to fight tumor growth, contain infections and treat immunodeficiencies.
目前已经明确，有效的免疫反应需要涉及多种信号的细胞间相互作用。此处综述的数据表明，CD40-CD40L相互作用对于CD4 T细胞依赖性效应功能的发展至关重要。缺乏这种重要的相互作用会导致CD4 T细胞的激活大幅减少，而这些分子的成功相互作用则会导致这些T细胞的完全激活。因此，CD40-CD40L相互作用的缺失会导致T细胞效应受损，如对B细胞分化和类别转换的辅助、单核细胞和巨噬细胞的激活以产生细胞因子并杀死细胞内病原体，以及自身反应性T细胞的激活以引发自身免疫反应。表I列出了在成功的免疫反应中由CD40-CD40L相互作用控制的T细胞效应功能。目前呈现的数据表明，CD40-CD40L相互作用在早期信号事件中发挥作用，在这些事件中，这种相互作用是诱导抗原呈递细胞（APC）上共刺激分子表达所必需的。一种可能的事件序列是，像树突状细胞（DC）这样的APC在损伤或感染部位摄取抗原并迁移至淋巴结，在那里它们将与MHC II类分子结合的抗原呈递给未成熟T细胞。这导致T细胞上CD40L的表达。T细胞上新表达的CD40L与APC上的CD40的结合导致APC共刺激活性的表达。此时，APC提供的共刺激信号通过CD28/CTLA-4被T细胞接收，这促使细胞进入细胞周期并完成T细胞激活。由此激活的T细胞现在可以与B细胞进入二级同源CD40-CD40L依赖性效应识别，以转换Ig类别，与巨噬细胞相互作用以产生细胞因子，以及与携带相同抗原的新DC相互作用以上调共刺激活性。对T细胞上CD40L表达和APC上共刺激活性的严格调节将防止不需要的旁观者T细胞的激活。在该模型中，用同源抗原致敏的APC的激活与针对该抗原的T细胞的激活的耦合为免疫反应的启动提供了额外的调节步骤。这也表明将有有限数量的T细胞/APC被激活，两者在本质上都是特异性的。这一额外步骤对于预防自身免疫反应可能很重要。此外，CD40L似乎独特地发挥这一作用这一事实表明，可以针对该分子开发治疗自身免疫性疾病和预防移植排斥的选择性免疫疗法。另一方面，可以开发针对CD40的方法来上调APC上的共刺激活性，以对抗肿瘤生长、控制感染和治疗免疫缺陷。
