Immune regulation by OX40/OX40 ligand system

OX40是一种重要的共刺激分子，表达于活化的T细胞上，在体外对T细胞的激活起重要作用。然而，OX40与其配体OX40L相互作用的体内功能意义仍不清楚。为了研究OX40L在体内免疫应答中的作用，我们建立了OX40L缺陷小鼠和一种封闭的抗OX40L单抗MGP34。经CD40和抗IgM刺激后，脾B细胞表达OX40L，而仅CD40结扎能诱导树突状细胞表达OX40L。OX40L缺陷和MGP34处理的小鼠，导致蛋白质和同种抗原同时启动的T细胞的召回反应明显受到抑制，KLH特异性免疫球蛋白的产生显著减少。受损的T细胞启动也伴随着Th1和Th2细胞因子的减少。此外，来自突变小鼠的抗原提呈细胞(APC)显示出内在的APC功能受损，证明了OX40L在T细胞激活的启动和效应阶段的重要性。综上所述，这些结果提供了令人信服的证据，证明表达在APC上的OX40L在活体抗原特异性T细胞反应中发挥关键作用。此外，我们还研究了OX40L缺乏或阻断OX40-OX40L相互作用在实验性自身免疫性脑炎(EAE)发病机制中的作用。与野生型或对照抗体处理的小鼠相比，OX40L缺陷和MGP34处理的小鼠在EAE期间表现出较少的症状和快速的恢复。这些结果提示OX40L可能在自身免疫性疾病如EAE的发病机制中起重要作用。

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.