National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
J Virol. 2012 Jul;86(13):7060-71. doi: 10.1128/JVI.00164-12. Epub 2012 May 2.
Persistent viral infections often overburden the immune system and are a major cause of disease in humans. During many persistent infections, antiviral T cells are maintained in a state of immune exhaustion characterized by diminished effector and helper functions. In mammalian systems, an extensive immune regulatory network exists to limit unwanted, potentially fatal immunopathology by inducing T cell exhaustion. However, this regulatory network at times overprotects the host and fosters viral persistence by severely dampening adaptive immune responsiveness. Importantly, recent studies have shown that T cell exhaustion is mediated in part by host immunoregulatory pathways (e.g., programmed death 1 [PD-1], interleukin 10 [IL-10]) and that therapeutic blockade of these pathways either before or during persistent infection can promote viral clearance. Transforming growth factor beta (TGF-β) is another immunosuppressive cytokine known to impede both self- and tumor-specific T cells, but its role in regulating antiviral immunity is not entirely understood. In this study, we inhibited TGF-β with three potent antagonists to determine whether neutralization of this regulatory molecule is a viable approach to control a persistent viral infection. Our results revealed that these inhibitors modestly elevate the number of antiviral T cells following infection with a persistent variant of lymphocytic choriomeningitis virus (LCMV) but have no impact on viral clearance. These data suggest that therapeutic neutralization of TGF-β is not an efficacious means to promote clearance of a persistent viral infection.
持续性病毒感染通常会给免疫系统带来过重负担，是导致人类疾病的主要原因之一。在许多持续性感染中，抗病毒 T 细胞处于免疫衰竭状态，其效应器和辅助功能减弱。在哺乳动物系统中，存在广泛的免疫调节网络，通过诱导 T 细胞衰竭来限制不必要的、潜在致命的免疫病理。然而，这种调节网络有时会过度保护宿主，通过严重抑制适应性免疫反应来促进病毒持续存在。重要的是，最近的研究表明，T 细胞衰竭部分是由宿主免疫调节途径（如程序性死亡 1 [PD-1]、白细胞介素 10 [IL-10]）介导的，在持续性感染之前或期间，这些途径的治疗性阻断可以促进病毒清除。转化生长因子-β（TGF-β）是另一种已知抑制自身和肿瘤特异性 T 细胞的免疫抑制细胞因子，但它在调节抗病毒免疫中的作用尚不完全清楚。在这项研究中，我们用三种有效的拮抗剂抑制 TGF-β，以确定中和这种调节分子是否是控制持续性病毒感染的可行方法。我们的结果表明，这些抑制剂在感染持续性淋巴细胞性脉络丛脑膜炎病毒（LCMV）变体后，适度增加了抗病毒 T 细胞的数量，但对病毒清除没有影响。这些数据表明，TGF-β的治疗性中和不是促进持续性病毒感染清除的有效方法。
