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

我们研究的长期目标是了解急性病毒感染的机制 诱导强大的免疫反应，希望从感染模型中获得的知识可以 申请改进疫苗接种策略。我们之前的研究，使用小鼠的淋巴细胞模型 脉络膜脑膜炎病毒(LCMV)感染，表明急性病毒感染诱发的 初级和记忆性CD8 T细胞反应的幅度比之前认为的要大。我们发现这些 抗病毒记忆CD8细胞即使在没有T细胞受体-MHC-I类的情况下也能长期存活 互动。现在越来越清楚的是，一些感染可以引发显著的T细胞反应，即使在 缺乏共刺激分子或专业的APC帮助。其潜在机制尚不清楚。至 为了更好地理解这些机制，我们开始描述可能导致 病毒感染时T细胞反应增强。我们发现感染诱导的I型干扰素(IFNod13)(A) 有助于增强CD8 T细胞的反应和(B)导致早期的NAFVE T细胞的短暂激活 感染。我们推测，这种IFNcdl3介导的天然CD8 T细胞增敏可能提供了一种 增强对抗原的反应能力的附加信号。因此，天然的CD8 T细胞可能 即使在没有共同刺激和或专业的APC帮助的情况下，也能很好地响应 感染。这一提议旨在通过以下假设来检验这一点：(1)幼稚的CD8 T 当细胞被感染诱导的ifncdl3致敏时，它们的激活阈值可能会降低，反应更好。 对于同源抗原刺激，(2)IFNcz/13受体阳性(IFNRc_/13+/+)CD8 T细胞可能具有 与受体阴性(IFNRcd13-/-)CD8 T细胞相比，在诱导免疫应答中具有选择性优势 病毒感染，以及，(3)IFNRcd13+/+CD8 T细胞可能变得不那么依赖专业的APC 在抗病毒反应中比IFNRcdI3-/-CD8 T细胞更有帮助。 这些研究将为深入了解病毒中旁观者T细胞激活的生物学后果提供依据 感染以及先天免疫和获得性免疫之间的相互作用机制。这项工作有 对改进疫苗接种战略的影响，并为今后旨在 了解免疫记忆产生的机制及其对人类的意义 和动物健康。

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 (IFNodl3)(a) helps potentiate the CD8 T cell response and (b) cause a transient activation of na'fve T cells early after infection. We hypothesize that this IFNcdl3 mediated sensitization of na'fve CD8 T cells may provide an additional signal that potentiates the ability to respond to antigen. As a result, the na'fve 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 IFNcdl3 may lower their activation threshold and respond better to cognate antigenic stimulus, (2) that IFNcz/13receptorpositive (IFNRc_/13+/+)CD8 T cells may have a selective advantage over receptor negative (IFNRcdl3-/-) CD8 T cells in eliciting immune response during viral infection, and, (3) that IFNRcdl3+/+ CD8 T cells may become less dependent upon professional APC help than IFNRcdI3-/- 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.