Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection.
Multiple Inhibitory Pathways Contribute to Lung CD8+ T Cell Impairment and Protect against Immunopathology during Acute Viral Respiratory Infection.
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DOI：
10.4049/jimmunol.1502115
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发表时间：
2016-07-01
期刊：
影响因子：
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通讯作者：
Williams JV
中科院分区：
文献类型：
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作者：
Erickson JJ;Rogers MC;Tollefson SJ;Boyd KL;Williams JV
病毒是下呼吸道感染 (LRI) 的常见原因。程序性细胞死亡-1 (PD-1) 信号传导导致急性病毒 LRI 期间肺 CD8+ T 细胞 (TCD8) 功能损伤，但 TCD8 损伤在病毒清除和免疫病理学中的作用尚不清楚。我们现在发现，人类偏肺病毒 (HMPV) 感染会诱导病毒特异性肺 TCD8，该 TCD8 无法产生效应细胞因子或在感染后期脱粒，即使在没有 PD-1 信号传导的情况下，功能也只有最小程度的增加。受损的肺 TCD8 上调多种抑制性受体，包括 PD-1、LAG-3、TIM-3 和 2B4。此外，即使在病毒清除后，这些受体的共表达仍持续增加，大多数病毒特异性肺TCD8在感染后第14天表达≥3个抑制性受体。病毒感染还增加了气道上皮细胞和抗原呈递细胞抑制性配体的表达，进一步建立了抑制环境。体外抗体阻断表明，多种抑制性受体会导致 HMPV 或流感病毒感染引起的 TCD8 损伤。体内阻断 TIM-3 信号传导无法增强 TCD8 功能或降低病毒滴度。然而，在 PD-1 缺陷小鼠中阻断 LAG-3 可恢复 TCD8 效应器功能，但会增加肺部病理学，表明 LAG-3 在体内介导肺 TCD8 损伤，并有助于在病毒清除过程中免受免疫病理学影响。这些结果表明，精心策划的通路网络在病毒 LRI 期间改变了肺 TCD8 功能，其中 PD-1 和 LAG-3 发挥着重要作用。肺部 TCD8 损伤可能会阻止免疫病理学，但也会导致复发性肺部感染。
Viruses are frequent causes of lower respiratory infection (LRI). Programmed cell death-1 (PD-1) signaling contributes to pulmonary CD8+ T cell (TCD8) functional impairment during acute viral LRI, but the role of TCD8 impairment in viral clearance and immunopathology is unclear. We now find that human metapneumovirus (HMPV) infection induces virus-specific lung TCD8 that fail to produce effector cytokines or degranulate late after infection, with minimally increased function even in the absence of PD-1 signaling. Impaired lung TCD8 upregulated multiple inhibitory receptors, including PD-1, LAG-3, TIM-3, and 2B4. Moreover, co-expression of these receptors continued to increase even after viral clearance, with most virus-specific lung TCD8 expressing ≥3 inhibitory receptors on day 14 post-infection. Viral infection also increased expression of inhibitory ligands by both airway epithelial cells and antigen presenting cells, further establishing an inhibitory environment. In vitro antibody blockade revealed that multiple inhibitory receptors contribute to TCD8 impairment induced by either HMPV or influenza virus infection. In vivo blockade of TIM-3 signaling failed to enhance TCD8 function or reduce viral titers. However, blockade of LAG-3 in PD-1-deficient mice restored TCD8 effector functions but increased lung pathology, indicating that LAG-3 mediates lung TCD8 impairment in vivo and contributes to protection from immunopathology during viral clearance. These results demonstrate that an orchestrated network of pathways modifies lung TCD8 functionality during viral LRI, with PD-1 and LAG-3 serving prominent roles. Lung TCD8 impairment may prevent immunopathology but also contribute to recurrent lung infections.