Early events regulating post-viral immunopathology

 描述(由申请人提供)：在清除呼吸道病毒感染的过程中，免疫反应的受控收缩对于消退炎症和限制肺损伤至关重要。抗病毒效应器CD8+T细胞收缩和抑制效应器功能的动力学似乎是在初始激活初始T细胞期间编程的，可能在此之前。在免疫反应的其他负性调节因子中，人们早就认识到，肿瘤坏死因子-α信号在CD8+效应T细胞的收缩中发挥着重要作用，尽管涉及的确切机制尚不清楚。我们已经证明，肿瘤坏死因子程序性收缩的关键时间发生在最初识别抗原后的24-48小时内，此后几乎没有免疫调节作用。此外，关键的来源是 这种早期产生的肿瘤坏死因子是初始识别抗原时的原始CD8+T细胞。我们假设，初始CD8+T细胞产生早期肿瘤坏死因子爆发的能力严重依赖于感染前宿主环境中的稳态I型干扰素信号。干扰素介导的初始CD8+T细胞对早期爆发的肿瘤坏死因子-α的调节是相当复杂的，并且似乎依赖于胸腺后外周T细胞的“许可”，在此期间，结构性低水平干扰素的产生的影响赋予了启动这一重要的早期肿瘤坏死因子应答的倾向。我们认为这涉及到这一关键活动的幼稚T细胞的表观遗传“许可”。这一建议的基本假设是，来自宿主环境的信号通过表观遗传事件影响初始CD8+T细胞，这些事件直接影响病毒感染期间和之后T细胞反应和效应器活动的收缩动力学，从而限制肺损伤和免疫病理学。

 DESCRIPTION (provided by applicant): The controlled contraction of immune responses during the clearance of respiratory virus infection is critical to resolution of inflammation and te limitation of lung injury. The kinetics of antiviral effector CD8+ T cell contraction, and dampenin of effector function, appears to be programmed during the initial activation of naive T cells, and possibly prior. Among other negative regulators of immune responses, it has long been appreciated that TNF-alpha signaling plays an important role in contraction of CD8+ effector T cells, though the precise mechanisms involved remain unclear. We've shown that the critical timing of TNF-programmed contraction occurs within the first 24-48 hours after initial antigen recognition, and plays little immunoregulatory role thereafter. Furthermore, the critical source of this early burst of TNF production is the naive CD8+ T cell upon initial antigen recognition. We hypothesize that the ability of the naive CD8+ T cell to produce an early TNF burst is critically dependent upon homeostatic type I interferon signaling in the host milieu prior to infection. The IFN-mediated regulation of the early burst of TNF-α by naive CD8+ T cells is quite complex, and appears dependent upon post-thymic peripheral T cell "licensing", during which the impact of constitutive low-level IFN production confers the tendency to mount this important early TNF response. We propose that this involves epigenetic "licensing" of naive T cells for this critical activity. The fundamental hypothesis of this proposal is that signals from the host milieu impinge upon naive CD8+ T cell through epigenetic events, which have a direct impact on the kinetics of the contraction of the T cell responses and effector activities during and after viral infection, serving to limit lung injury and immunopathology.