Vinay Dass S, Kwon Byoung S
Department of Ophthalmology, LSU Eye Center, Louisiana State University Health Sciences Center School of Medicine, New Orleans, USA.
Int J Hematol. 2006 Jan;83(1):23-8. doi: 10.1532/IJH97.05125.
T-cell activation in the absence of costimulation is futile because T-cells deprived of costimulatory signals enter a state of unresponsiveness or anergy. The interaction of 4-1BB and 4-1BB ligand (4-1BBL) activates an important costimulatory pathway with diverse and important roles in immune regulation. Signals relayed through 4-1BB generate strong CD8(+) T-cell responses rather than CD4(+) T-cell responses; this action results in cytokine induction and promotes T-cell survival. In recent years, 4-1BB-mediated immune regulation has gained great significance because of the seemingly contradictory dual roles of agonistic anti-4-1BB in vivo disease models. To date, agonistic 4-1BB monoclonal antibody has shown therapeutic potential against a variety of tumors, CD4(+) T-cell-mediated autoimmune diseases, and chronic graft-versus-host disease. In addition, blockade of 4-1BB/4-1BBL interaction has produced therapeutic effects against coxsackievirus-induced myocardial inflammation, herpetic stromal keratitis, and graft rejection. We propose that the dual roles of agonistic anti-4-1BB--an enhanced effector function and a suppressor function--are mediated by a novel CD11c(+)CD8(+) T-cell population.
在缺乏共刺激的情况下，T细胞激活是无效的，因为被剥夺共刺激信号的T细胞会进入无反应状态或失能状态。4-1BB与4-1BB配体（4-1BBL）的相互作用激活了一条重要的共刺激途径，在免疫调节中具有多种重要作用。通过4-1BB传递的信号产生强烈的CD8(+) T细胞反应而非CD4(+) T细胞反应；这种作用导致细胞因子诱导并促进T细胞存活。近年来，由于激动性抗4-1BB在体内疾病模型中看似矛盾的双重作用，4-1BB介导的免疫调节具有了重大意义。迄今为止，激动性4-1BB单克隆抗体已显示出对多种肿瘤、CD4(+) T细胞介导的自身免疫性疾病以及慢性移植物抗宿主病的治疗潜力。此外，阻断4-1BB/4-1BBL相互作用已对柯萨奇病毒诱导的心肌炎症、疱疹性基质性角膜炎和移植排斥产生了治疗效果。我们提出，激动性抗4-1BB的双重作用——增强的效应功能和抑制功能——是由一种新型的CD11c(+)CD8(+) T细胞群体介导的。
