ROLE OF TYPE-I IFN'S IN ANTIVIRAL CD8 CELL RESPONSE

描述（由申请人提供）：我们研究的长期目标是了解急性病毒感染诱导强效免疫反应的机制，希望从感染模型中获得的知识可以应用于改进疫苗接种策略。我们之前的研究，使用淋巴细胞性脉络丛脑膜炎病毒（LCMV）感染的小鼠模型，证明急性病毒感染诱导的原发性和记忆性CD8 T细胞反应比之前认为的要高得多。我们发现，即使在没有T细胞受体- mhc I类相互作用的情况下，这些抗病毒记忆CD8细胞也能持续很长时间。现在越来越清楚的是，即使在没有共刺激分子或专业APC帮助的情况下，一些感染也能引起显著的T细胞反应。潜在的机制尚不清楚。为了更好地理解这些机制，我们开始描述可能有助于增强病毒感染中T细胞反应的事件。我们发现感染诱导的i型干扰素（IFN α / β） (a)有助于增强CD8 T细胞的反应，(b)在感染后早期引起幼稚T细胞的短暂激活。我们假设，这种IFN α / β介导的初始CD8 T细胞致敏可能提供了一个额外的信号，增强了对抗原的反应能力。因此，在感染条件下，即使没有共同刺激和/或专业APC帮助，初始CD8 T细胞也可能反应良好。本研究旨在通过以下假设来验证这一点：(1)初始CD8 T细胞在感染诱导的IFN α / β致敏后，可能会降低其激活阈值，并对同源抗原刺激做出更好的反应；(2)IFN α / β受体阳性(IFNR ?/？+/+) CD8 T细胞可能比受体阴性（IFNR α / β -/-） CD8 T细胞在病毒感染期间引发免疫反应方面具有选择性优势，并且(3)在抗病毒反应期间，IFNR α / β +/+ CD8 T细胞可能比IFNR α / β -/- CD8 T细胞更少依赖于专业APC帮助。这些研究将深入了解病毒感染中旁观者T细胞活化的生物学后果，以及先天免疫和适应性免疫之间的串扰机制。这项工作对改进疫苗接种策略具有重要意义，并为未来旨在了解免疫记忆产生机制的研究奠定了基础，对人类和动物健康具有重要意义。

DESCRIPTION (provided by applicant): The long-term objectives of our research are to understand the mechanisms by which acute viral infections induce potent immune responses with a hope that the knowledge gained from infectious models can be applied for improving vaccination strategies. Our previous studies, using mouse models of lymphocytic choriomeningitis virus (LCMV) infection, demonstrated that acute viral infections induce a much higher magnitude of primary and memory CD8 T cell responses than was previously thought. We found that these anti-viral memory CD8 cells persist for extended periods even in the absence of T cell receptor-MHC class I interactions. Now it is becoming clear that some infections can elicit significant T cell responses even in the absence of costimulatory molecules or professional APC help. The underlying mechanisms are not clear. To better understand these mechanisms, we started characterizing possible events that may contribute to the enhanced T cell response in viral infection. We found that infection-induced type-I interferons (IFN alpha/beta) (a) helps potentiate the CD8 T cell response and (b) cause a transient activation of naive T cells early after infection. We hypothesize that this IFN alpha/beta mediated sensitization of naive CD8 T cells may provide an additional signal that potentiates the ability to respond to antigen. As a result, the naive CD8 T cells may respond well even in the absence of co-stimulatory and or professional APC help under the conditions of infection. This proposal is aimed at testing this by pursuing the following hypotheses: (1) that naive CD8 T cells, upon sensitization by infection-induced IFN alpha/beta may lower their activation threshold and respond better to cognate antigenic stimulus, (2) that IFN alpha/beta receptor positive (IFNR ?/? +/+) CD8 T cells may have a selective advantage over receptor negative (IFNR alpha/beta -/-) CD8 T cells in eliciting immune response during viral infection, and, (3) that IFNR alpha/beta +/+ CD8 T cells may become less dependent upon professional APC help than IFNR alpha/beta -/- CD8 T cells during an anti-viral response. These studies will provide insight into the biological consequences of bystander T cell activation in viral infections and the mechanisms of cross-talk between innate and adaptive immunity. This work has implications for improving vaccination strategies and provides groundwork for future studies aimed at understanding the mechanisms involved in generation of immune memory and have significance for human and animal health.