TYPE I INTERFERON REGULATION OF IMMUNOPATHOLOGY IN INFLUENZA PNEUMONIA

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 流感肺炎导致相当大的肺损伤，其中很大一部分是由远端呼吸道的CD8+T细胞抗原识别介导的。由抗原特异的CD8+T细胞产生的TNF-α似乎是导致这种免疫病理的主要效应活性，我们已经研究了CD94/NKG2A通过其受体Qa-1b参与对CD8+TNF产生的负调控。NKG2A在流感感染小鼠肺部的CD8+T细胞上被诱导表达，随着病毒的清除，表达水平下降。CD8+T细胞在MLN和脾组织中未见表达。阻断NKG2a后，抗病毒CD8+T细胞产生的肿瘤坏死因子显著增加，其配体Qa-1b缺乏的小鼠在严重感染流感并转移激活的效应T细胞后，表现出明显的免疫病理变化。此外，阻断NKG2A的结扎可在无感染病毒的情况下，通过激活CD8+效应细胞对肺泡抗原的识别而导致病理增强。这些数据表明，CD94/NKG2A向激活的CD8+T细胞传递了一个重要的生物学信号，限制了它们在体内的效应活性，并减轻了严重流感感染的免疫病理学。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Influenza pneumonia results in considerable lung injury, a significant component of which is mediated by CD8+ T cell antigen recognition in the distal airways. TNF-alpha produced by antigen-specific CD8+ T cells appears to be the primary effector activity responsible for this immunopathology, and we have examined the negative regulation of CD8+ TNF production by CD94/NKG2A engagement by its receptor, Qa-1b. NKG2A expression is induced on CD8+ T cells in the lungs of influenza-infected mice, and expression levels fall as the virus is cleared. Expression was not observed in CD8+ T cells harvested from MLN or spleen at any time. TNF production by antiviral CD8+ T cells was significantly enhanced by NKG2A blockade, and mice deficient in its ligand, Qa-1b, manifest significantly greater immunopathology upon severe infection with influenza followed by transfer of activated effector CD8+ T cells. Furthermore, blockade of NKG2A ligation resulted in enhancement of pathology induced by activated CD8+ effector cell recognition of alveolar antigen in the absence of infectious virus. These data demonstrate that CD94/NKG2A transduces a biologically important signal to activated CD8+ T cells which limits their effector activity in vivo and mitigates immunopathology in severe influenza infection.