T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.
T-cell exhaustion, co-stimulation and clinical outcome in autoimmunity and infection.
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DOI：
10.1038/nature14468
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发表时间：
2015-07-30
期刊：
影响因子：
64.8
通讯作者：
Smith KG
中科院分区：
文献类型：
--
作者：
McKinney EF;Lee JC;Jayne DR;Lyons PA;Smith KG
自身免疫性疾病和感染性疾病的临床病程差异很大，甚至在病情相同的人之间也是如此。对这种异质性的分子基础的了解可能导致监测和治疗方面的重大改进。在慢性感染期间，T细胞耗尽的过程抑制了免疫反应，促进了病毒的持续。在这里，我们表明，反映CD8 T细胞耗竭的转录信号与慢性病毒感染清除不良有关，但反过来预测多种自身免疫性疾病的预后较好。慢性感染期间CD8T细胞耗尽的发展既是由抗原的持久性推动的，也是由缺乏辅助的“帮助”信号驱动的。在自身免疫方面，我们发现，在CD4T细胞共刺激的证据明显的地方，CD8T细胞耗尽的证据减少。我们可以通过改变T细胞抗原受体的持续刺激和CD2诱导的特异性共刺激在体外提供给人CD8 T细胞的平衡来重现衰竭特征，这表明每个过程在决定自身免疫性疾病的结果中都发挥了作用。由CD2诱导的共刺激所驱动的“非耗竭”T细胞状态被与耗竭相关的抑制性受体PD-1所传递的信号所降低，这表明诱导耗竭可能是自身免疫和炎症性疾病的一种治疗策略。通过在独立数据集中表达共刺激/衰竭信号的最佳替代标记物，我们确认在感染(丙型肝炎病毒)和疫苗接种(黄热病、疟疾、流感)的治疗中具有良好的临床结果或反应，但在自身免疫和炎症性疾病(1型糖尿病、抗中性粒细胞胞浆抗体相关血管炎、系统性红斑狼疮、特发性肺纤维化和登革热出血热)中结果较差。因此，T细胞耗竭在决定自身免疫性疾病的预后中起着核心作用，对这一过程的靶向操作可能会带来新的治疗机会。
The clinical course of autoimmune and infectious disease varies greatly, even between individuals with the same condition. An understanding of the molecular basis for this heterogeneity could lead to significant improvements in both monitoring and treatment. During chronic infection the process of T-cell exhaustion inhibits the immune response, facilitating viral persistence. Here we show that a transcriptional signature reflecting CD8 T-cell exhaustion is associated with poor clearance of chronic viral infection, but conversely predicts better prognosis in multiple autoimmune diseases. The development of CD8 T-cell exhaustion during chronic infection is driven both by persistence of antigen and by a lack of accessory ‘help’ signals. In autoimmunity, we find that where evidence of CD4 T-cell co-stimulation is pronounced, that of CD8 T-cell exhaustion is reduced. We can reproduce the exhaustion signature by modifying the balance of persistent stimulation of T-cell antigen receptors and specific CD2-induced co-stimulation provided to human CD8 T cellsin vitro, suggesting that each process plays a role in dictating outcome in autoimmune disease. The ‘non-exhausted’ T-cell state driven by CD2-induced co-stimulation is reduced by signals through the exhaustion-associated inhibitory receptor PD-1, suggesting that induction of exhaustion may be a therapeutic strategy in autoimmune and inflammatory disease. Using expression of optimal surrogate markers of co-stimulation/exhaustion signatures in independent data sets, we confirm an association with good clinical outcome or response to therapy in infection (hepatitis C virus) and vaccination (yellow fever, malaria, influenza), but poor outcome in autoimmune and inflammatory disease (type 1 diabetes, anti-neutrophil cytoplasmic antibody-associated vasculitis, systemic lupus erythematosus, idiopathic pulmonary fibrosis and dengue haemorrhagic fever). Thus, T-cell exhaustion plays a central role in determining outcome in autoimmune disease and targeted manipulation of this process could lead to new therapeutic opportunities.