摘要
CD1d-restricted natural killer T(NKT)cells are innate-like T lymphocytes with protective or pathogenic roles in the development of influenza pneumonia.Here,we show that lung-infiltrated and activated NKT cells are the major cellular source of LIGHT/TNFSF14,which determines the severity of pulmonary pneumonia by highly deteriorative influenza A virus(IAV)infection.Compared to wild-type mice,LIGHT^(-/-)mice exhibit much lower morbidity and mortality to IAV,due to alleviated lung damage and reduced apoptosis of alveolar macrophages(AMs).LIGHT preferentially promotes cell death of lymphotoxin β receptors positive(LTβR^(+))AMs but not herpesvirus entry mediator positive(HVEM^(+))AMs.Therefore,these results suggest that NKT-derived LIGHT augments cell death of the tissue protective AMs in exacerbating lung pathology and susceptibility to fatal influenza infection.Suppression of LIGHT signaling might be a viable option in the treatment of influenza-associated acute respiratory distress syndrome.
CD1d限制的NKT细胞是一类固有免疫样T淋巴细胞,在流感引起的肺炎中可以起到保护或阻碍的作用.本研究发现浸润到肺并激活的NKT细胞是LIGHT/TNFSF14的主要细胞来源,LIGHT加重了高致病性流感病毒感染(IAV)造成的肺部炎症.与野生型小鼠相比,LIGHT^(-/-)小鼠由于减少了肺泡巨噬细胞(AM)的凋亡从而减轻了肺损伤,因此对IAV的发病率和死亡率要显著降低.LIGHT优先促进LTβR+,而不是HVEM+的AM死亡.这些结果表明,NKT来源的LIGHT增加了组织保护性AM的细胞死亡,从而加重了肺部病理和对高致病性流感病毒的易感性.封闭LIGHT信号可能是治疗流感相关急性呼吸窘迫综合征(ARDS)可行的选择.
作者
Li-Na Shi
Yihua Zhou
Chao Wu
Wenfeng Huang
Feng Yuan
Jianjun Chen
Zhiwei Wu
Wenwei Tu
Hairong Chen
Quanjiao Chen
Mingzhao Zhu
Hua Peng
Yan Yang
Hong Tang
石丽娜;周乙华;吴超;黄文锋;袁峰;陈建军;吴稚伟;涂文伟;陈海荣;陈全姣;朱明昭;彭华;杨艳;唐宏(CAS Key Laboratory of Molecular Virology and Immunology,Institut Pasteur of Shanghai,Chinese Academy of Sciences,Shanghai 200031,China;Department of Infectious Disease,Nanjing Drum Tower Hospital of Nanjing University Medical School,Nanjing 210008,China;Wuhan Institute of Virology,Chinese Academy of Sciences,Wuhan 430071,China;CAS Key Laboratory of Infection and Immunity,Institute of Biophysics,Chinese Academy of Sciences,Beijing 100101,China;Center for Public Health Research and State Key Laboratory of Analytical Chemistry for Life Sciences,Nanjing University,Nanjing 210093,China;Department of Paediatrics and Adolescent Medicine,The University of Hong Kong,Hong Kong 999077,China;The Pateurien College,Soochow University,Suzhou 215006,China;The Graduate School of University of Chinese Academy of Sciences,Beijing 100049,China)
基金
supported by the Chinese Academy of Sciences(XDB29030301)
the Ministry of Science and Technology(2018ZX10101004002004 and 2018YFC1200703)
the National Natural Science Foundation of China(31321001,31621061,81590764,and 31400755)。
