Innate Regulation of CD8+ T Cell Effector Activites

感染呼吸道病毒，如流感、冠状病毒和其他病毒，会导致相当大的 肺免疫病理学，其中很大一部分是由宿主特异的免疫反应引起的。 1型干扰素(干扰素-a(3))是大多数病毒先天免疫反应的重要组成部分。 感染，大多数病毒株，包括高致病性流感株，已经进化 抑制或逃避这些防御的机制。除了直接抑制病毒复制外，类型 1干扰素具有多种其他免疫调节特性。然而，最近，它已经成为 显然，在实验性流感的T细胞反应背景下发生的肺损伤 在缺乏干扰素-a(3)受体的情况下，感染要严重得多，这不是 增强了病毒复制功能。我们的数据表明抑制NKG2A受体在CD8 T细胞上的表达 通常在病毒清除过程中被诱导的细胞，在没有病毒的情况下不会被显著地诱导 干扰素-A3受体。此外，NKG2A还可提高CD8T细胞的激活阈值 当NKG2A与其同源受体结合被阻断时，增强的T细胞效应器活性是 观察到的。CD8 T细胞诱导抑制性NKG2A表达的条件探讨 流感感染提示，在存在干扰素-a(3在区域淋巴中)的情况下，最初的抗原识别 节点可能是必需的，但直到细胞到达 周围(即肺实质)。为了了解1型干扰素在抑制血管紧张素转换酶活性中的作用 肺部免疫病理在呼吸道病毒感染时，我们将检验初始抗原的假设 在存在1型干扰素的情况下，CD8T细胞抑制NKG2a被“启动” 表达，但CD8 T细胞上的实际受体表达需要肺内的抗原识别 实质，可能位于专业的抗原提呈细胞上，如树突状细胞。具体来说，我们 建议分析I型干扰素对CD8T细胞NKG2a调节的直接和间接作用 CD8T细胞的表达和免疫病理潜能，并了解其调节机制 通过干扰素-α(3)表达NKG2A，这将为微调细胞周期的机制提供重要的线索 抗病毒适应性免疫反应，以优化病毒清除并将组织损伤降至最低，这可能 在这个过程中发生。

Infection with respiratory viruses, such as with influenza, coronavirus, and others, results in considerable pulmonary immunopathology, a large component of which results from the host specific immune responses,. Type 1 interferons (IFN-a(3) represent an important component of the innate immune response to most virus infections, and most strains of virus, including the highly pathogenic strains of influenza, have evolved mechanisms to suppress or evade these defenses. In addition to the direct inhibition of viral replication, type 1 interferons possess a variety of other immunomodulatory properties. Recently, however, it has become apparent that lung injury which occurs in the context of the T cell response to experimental influenza infection is considerably more severe in the absence of the IFN-a(3 receptor, and this is not a result of enhanced viral replication. Our data indicate that expression of the inhibitory NKG2A receptor on CD8+ T cells, which is usually induced during the course of viral clearance, is not significantly induced in the absence of the IFN-a3-receptor. Furthermore, the activation threshold of CD8+ T cells is increased by NKG2A activity, and when NKG2A binding to its cognate receptor is blocked, enhanced T cell effector activity is observed. Examination of the requirements for induction of inhibitory NKG2A expression by CD8+ T cells in influenza infection suggests that initial antigen recognition in the presence of IFN-a(3 in the regional lymph node is probably required, though expression is not observed until the cells reach the effector site in the periphery (i.e. the lung parenchyma). In order to understand the role of type 1 interferons on the inhibition of pulmonary immunopathology in respiratory virus infection, we will test the hypothesis that initial antigen engagement in the presence of type 1 interferon results in "priming" for CD8+ T cell inhibitory NKG2A expression, but that actual receptor expression on CD8+ T cells requires antigen recognition in the lung parenchyma, probably on professional antigen-presenting cells such as dendritic cells. Specifically we propose to analyze the direct and indirect effects of type I interferon on regulation of CD8+ T cell NKG2A expression and immunopathologic potential, and to understand the mechanisms of regulation of CD8+ T cell NKG2A expression by IFN-a(3. This will shed important light into the mechanisms of fine-tuning of the antiviral adaptive immune responses to optimize virus clearance and minimize tissue damage which may occur in the process.