Memory CD4 T Cells Direct Protective Responses to Influenza Virus in the Lungs through Helper-Independent Mechanisms
Memory CD4 T Cells Direct Protective Responses to Influenza Virus in the Lungs through Helper-Independent Mechanisms
复制标题
DOI：
10.1128/jvi.01069-10
复制
发表时间：
2010-09-15
影响因子：
5.4
通讯作者：
Farber, Donna L.
中科院分区：
文献类型：
--
作者：
Teijaro, John R.;Verhoeven, David;Farber, Donna L.
流感病毒特异性记忆 CD4 T 细胞是由自然感染和疫苗接种产生的，长期存在，并识别季节性和大流行性流感病毒株的决定因素。然而，这些长寿命流感病毒特异性记忆 CD4 T 细胞的保护潜力尚不清楚，包括 CD4 T 细胞辅助细胞或效应器功能在二次抗病毒反应中是否重要。在这里，我们证明了 H1N1 流感病毒特异性的记忆 CD4 T 细胞通过内在效应机制指导对流感病毒攻击的保护性反应，从而增强病毒清除、从亚致死感染中恢复，并全面保护免受致命攻击。具有流感病毒血凝素（HA）特异性记忆CD4 T细胞或多克隆流感病毒特异性记忆CD4 T细胞的小鼠表现出对流感病毒攻击的保护作用，这种攻击在B细胞缺陷小鼠中存在CD8消耗抗体的情况下以及当CD4 T细胞被转移到淋巴细胞缺陷RAG2（-/-）小鼠中时发生。此外，记忆 CD4 T 细胞的存在增强了肺部 T 细胞的募集和免疫反应。体内γ干扰素（IFN-γ）产生的中和消除了记忆CD4 T细胞介导的针对HA特异性记忆T细胞的流感病毒攻击的保护和多克隆记忆CD4 T细胞的异亚型保护。我们的结果表明，记忆 CD4 T 细胞可以通过动员肺部的免疫效应器来指导增强对流感病毒感染的保护，而与其辅助功能无关。这些发现通过促进长效保护性 CD4 T 细胞反应，对通用流感疫苗的产生具有重要意义。
Memory CD4 T cells specific for influenza virus are generated from natural infection and vaccination, persist long-term, and recognize determinants in seasonal and pandemic influenza virus strains. However, the protective potential of these long-lived influenza virus-specific memory CD4 T cells is not clear, including whether CD4 T-cell helper or effector functions are important in secondary antiviral responses. Here we demonstrate that memory CD4 T cells specific for H1N1 influenza virus directed protective responses to influenza virus challenge through intrinsic effector mechanisms, resulting in enhanced viral clearance, recovery from sublethal infection, and full protection from lethal challenge. Mice with influenza virus hemagglutinin (HA)-specific memory CD4 T cells or polyclonal influenza virus-specific memory CD4 T cells exhibited protection from influenza virus challenge that occurred in the presence of CD8-depleting antibodies in B-cell-deficient mice and when CD4 T cells were transferred into lymphocyte-deficient RAG2(-/-) mice. Moreover, the presence of memory CD4 T cells mobilized enhanced T-cell recruitment and immune responses in the lung. Neutralization of gamma interferon (IFN-gamma) production in vivo abrogated memory CD4 T-cell-mediated protection from influenza virus challenge by HA-specific memory T cells and heterosubtypic protection by polyclonal memory CD4 T cells. Our results indicate that memory CD4 T cells can direct enhanced protection from influenza virus infection through mobilization of immune effectors in the lung, independent of their helper functions. These findings have important implications for the generation of universal influenza vaccines by promoting long-lived protective CD4 T-cell responses.