Immune regulation by OX40/OX40 ligand system

OX 40是体外T细胞活化过程中重要的共刺激分子。然而，OX 40与其配体OX 40 L之间相互作用的体内功能意义仍不清楚。为了研究OX 40 L在体内免疫应答中的作用，我们产生了OX 40 L缺陷型小鼠和阻断性抗OX 40 L mAb MGP 34。在CD 40和抗IgM刺激后，在脾B细胞上证实了OX 40 L的表达，而只有CD 40连接能够诱导树突状细胞上的OX 40 L。OX 40 L缺陷和MGP 34处理的小鼠，产生了明显的抑制与蛋白质和同种异体抗原引发的T细胞的回忆反应，并显着减少KLH特异性IgG的生产。受损的T细胞引发也伴随着Th 1和Th 2细胞因子的同时减少。此外，来自突变小鼠的抗原呈递细胞（APC）揭示了受损的内在APC功能，证明了OX 40 L在T细胞活化的引发和效应阶段的重要性。总的来说，这些结果提供了令人信服的证据表明，OX 40 L，在APC上表达，在抗原特异性T细胞responses in vivo. Further，我们研究了OX 40 L-缺陷或阻断OX 40-OX 40 L相互作用的实验性自身免疫性脑炎（EAE），这是一个小鼠模型，为人类多发性硬化症的发病机制的影响。与野生型或对照Ab处理的小鼠相比，OX 40 L缺陷和MGP 34处理的小鼠在EAE期间表现出较少的症状和快速恢复。这些结果表明，OX 40 L可能在功能上参与了自身免疫性疾病，如EAE的发病机制。

OX40 expressed on activated T cells is known to be an important costimulatory molecule on T cell activation in vitro. However, the in vivo functional significance of the interaction between OX40 and its ligand, OX40L is still unclear. To investigate the role of OX40L during in vivo immune responses, we generated OX40L-deficient mice and a blocking anti-OX40L mAb, MGP34. OX40L expression was demonstrated on splenic B cells after CD40 and anti-IgM stimulation, while only CD40 ligation was capable of inducing OX40L on dendritic cells. OX40L-deficient and MGP34-treated mice, engendered apparent suppression of the recall reaction of T cells primed with both protein- and allo-antigens and a significant reduction in KLH-specific IgG production. The impaired T-cell-priming was also accompanied by a concomitant reduction of both Th1 and Th2 cytokines. Furthermore, antigen presenting cells (APCs) derived from the mutant mice revealed an impaired intrinsic APC function, demonstrating the importance of OX40L in both the priming and effector phases of T cell activation. Collectively, these results provide convincing evidence that OX40L, expressed on APCs, plays a critical role in antigen-specific T cell responses in vivo.Furthermore, we examined the effect of OX40L-deficiency or blockade of OX40-OX40L interaction in pathogenesis of experimental autoimmune encephalitis (EAE), which is a mouse model for human multiple sclerosis. OX40L-deficient and MGP34-treated mice showed less symptoms and rapid recovery during EAE as compared with wild type or control Ab-treated mice. These results suggest that OX40L may be functionally involved in the pathogenesis of autoimmune diseases such as EAE.