Experimental Medicine and Rheumtology, William Harvey Research Institute, Queen Mary University of London, London, UK.
Kennedy Institute of Rheumatology, Oxford University, Oxford, UK.
Cytokine. 2018 Jan;101:4-13. doi: 10.1016/j.cyto.2016.09.001. Epub 2016 Sep 14.
TNFα is a principal pro-inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms. Paradoxically, however, treatment with TNFα inhibitors can either have no clinical effects, or even exacerbate disease in some patients. The explanation for such contradictory outcomes may lay in how and which downstream signalling pathways are activated and drive disease. TNFα causes its effects by binding to either or both of two membrane-bound receptors, TNFR1 and TNFR2. Engagement of the receptors can induce cell death or cell proliferation. T cells both produce and respond to TNFα and depending on whether the cytokine is membrane-bound or soluble and the level of expression of its two receptors, the biological outcome can be distinct. In addition, polymorphisms in genes encoding TNFα and T cell signalling proteins can significantly impact the outcome of TNFα receptor engagement. Early studies revealed that effector T cells in patients with rheumatoid arthritis (RA) are hyporesponsive due to chronic exposure to TNFα. However, recent evidence indicates that the relationship between TNFα and T cell responses is complex and, at times, can be paradoxical. In addition, there is controversy as to the specific effects of TNFα on different T cell subsets. This review will summarise knowledge on how TNFα modulates T cell responses and the effect of engaging either of its two receptors. Furthermore, we discuss how such interactions can dictate the outcome of treatment with TNFα inhibitors.
肿瘤坏死因子-α（TNFα）是一种主要的促炎细胞因子，对感染的免疫至关重要。然而，其过度产生与自身免疫性疾病中的慢性炎症和疾病病理学有关。其致病作用的证据是通过以下事实得到验证的：在体内用治疗剂中和其可改善疾病并控制症状。然而，具有讽刺意味的是，用 TNFα 抑制剂治疗要么没有临床效果，要么甚至在一些患者中使疾病恶化。这种矛盾结果的解释可能在于哪些下游信号通路被激活并导致疾病。TNFα 通过与两种膜结合受体（TNFR1 和 TNFR2）中的一种或两种结合来发挥作用。受体的结合可以诱导细胞死亡或细胞增殖。T 细胞既能产生又能对 TNFα 作出反应，并且取决于细胞因子是膜结合的还是可溶性的，以及其两种受体的表达水平，生物学结果可以是不同的。此外，编码 TNFα 和 T 细胞信号蛋白的基因中的多态性可以显著影响 TNFα 受体结合的结果。早期研究表明，类风湿关节炎（RA）患者的效应 T 细胞由于长期暴露于 TNFα 而反应低下。然而，最近的证据表明，TNFα 与 T 细胞反应之间的关系是复杂的，有时甚至是矛盾的。此外，关于 TNFα 对不同 T 细胞亚群的具体作用存在争议。这篇综述将总结关于 TNFα 如何调节 T 细胞反应及其两种受体结合的作用的知识。此外，我们还讨论了这种相互作用如何决定 TNFα 抑制剂治疗的结果。
