Functional Analyses of Antiviral CD4+ T Cell Responses

描述（由申请人提供）：保护性免疫，无论是通过感染还是通过疫苗接种诱导，依赖于产生足够数量和足够质量的记忆性B & T细胞。这一过程的成功很大程度上依赖于CD4+ T细胞提供的“帮助”。CD4+ T细胞在协调适应性免疫反应中发挥核心作用，但其丰度被调节的机制、复发性抗原接触的重要性以及它们为CD8+ T细胞提供帮助的方式仍不确定。本应用程序的总体目标是(i)继续我们对体内CD4+ T细胞数量和质量如何受IFN调节的研究？以及它们如何受到体内与持久性病毒抗原接触的影响（目标1和2）；（ii）研究CD4+ T细胞如何为开发良好的抗病毒CD8+ T细胞记忆提供所需的帮助（目标3和4）。目的1。确定IFN有多直接？信号传导对原发性和记忆性CD4+ T细胞的丰度有深远的影响。我们已经证明CD4+ T细胞可以直接对IFN？在内存池中要多100倍。我们将在什么时候确定IFN的效果？是施加;结果是基因表达发生了什么变化；哪些细胞会产生这种重要的细胞因子。目标2。目的观察MHCⅱ类抗原长时间呈递对CD4+ T细胞数量和质量的影响。这是公认的，在慢性感染期间，持久抗原可以显著改变T细胞的反应。然而，在急性病毒感染的模型中，抗原持久性的问题还不太明确。我们发现MHC II类在急性病毒感染后数周内呈现病毒抗原。我们将测量持久性抗原对CD4+ T细胞功能的影响。抗原驱动的IFN？生产雕刻CD4+ T细胞的反应？目标3。研究病毒特异性和非特异性CD4+ T细胞提供的帮助。我的实验室是第一个证明CD4+ T细胞在急性病毒感染后建立CD8+ T细胞记忆中起关键作用的实验室之一，这一观察结果已被许多实验室证实和扩展。令人惊讶的是，CD4+ T细胞似乎能够以非特异性（“非同源”）的方式为CD8+ T细胞提供帮助。我们将比较CD4+ T细胞对病毒表位的特异性和不能识别病毒的CD4+ T细胞的帮助。目标4。确定IFN？是CD4+ T细胞帮助的关键媒介。最后的Aim汇集了两条线索：(i) CD4+ T细胞的帮助是发展良好的CD8+ T细胞记忆所必需的事实；（ii）我们最近发现IFN？对CD8+ T细胞记忆的发展至关重要。可能干扰素?是CD4+ T细胞帮助CD8+ T细胞记忆发展的“纽带”吗？IFN的作用是什么？特异性和非特异性CD4+辅助性T细胞相同？公共卫生相关性：CD4+ T细胞在调节对感染和疫苗接种的免疫反应中发挥核心作用。令人惊讶的是，我们并不确切地知道它们做了什么，以及它们是如何做到的。事实上，最近的一些数据表明，即使疫苗不刺激CD4+ T细胞反应，它们也可能很有效。这项拨款申请调查了几个关于重要的，但知之甚少的细胞的问题。

DESCRIPTION (provided by applicant): Protective immunity, whether induced by infection or by vaccination, relies on the generation of memory B & T cells in sufficient quantity, and of sufficient quality. The success of this process is heavily dependent on "help" that is provided by CD4+ T cells. CD4+ T cells play a central role in orchestrating the adaptive immune response but the mechanism by which their abundance is regulated, the importance of recurrent antigen contact, and the means by which they provide help to CD8+ T cells all remain uncertain. The overall goals of this application are (i) to continue our studies of how CD4+ T cell quantity and quality are regulated in vivo by IFN?, and how they are affected by in vivo contact with persistent virus antigen (Aims 1 & 2); and (ii) to investigate how CD4+ T cells provide the help that is required for the development of good antiviral CD8+ T cell memory (Aims 3 & 4). Aim 1. To determine how direct IFN? signaling exerts its profound effects on the abundance of primary and memory CD4+ T cells. We have shown that CD4+ T cells that can respond directly to IFN? are 100- fold more abundant in the memory pool. We will determine when the effect of IFN? is exerted; what changes in gene expression occur as a result; and which cells produce this important cytokine. Aim 2. To evaluate the effects of prolonged MHC class II antigen presentation on CD4+ T cell quantity and quality. It is well-established that, during chronic infection, persistent antigen can dramatically alter the T cell response. However, the issue of antigen persistence is much less well-defined in models of acute viral infection. We have found that MHC class II presents virus antigen for weeks after acute virus infection. We shall measure the effects of persistent antigen on CD4+ T cell functions. Does antigen- driven IFN? production sculpt the CD4+ T cell response? Aim 3. To investigate the help that is provided by virus-specific and non-specific CD4+ T cells. My lab was among the first to show that CD4+ T cells played a key role in establishing CD8+ T cell memory following acute virus infection, an observation that has been confirmed and extended by a number of labs. Surprisingly, CD4+ T cells seem to be able to provide help to CD8+ T cells in a non-specific ("noncognate") fashion. We shall compare the helpfulness of CD4+ T cells that are specific for a viral epitope, with the helpfulness of CD4+ T cells that cannot recognize the virus. Aim 4. To determine if IFN? is a key mediator of CD4+ T cell help. The final Aim draws together two threads: (i) the fact that CD4+ T cell help is required for the development of good CD8+ T cell memory and (ii) our recent finding that IFN? is vitally important for the development of CD8+ T cell memory. Might IFN? be the "link" by which CD4+ T cells help the development of CD8+ T cell memory? Is the role of IFN? the same for specific & non-specific CD4+ helper T cells? PUBLIC HEALTH RELEVANCE: CD4+ T cells play a central role in regulating the immune response to infection and vaccination. Surprisingly, we do not know exactly what they do, and how they do it. Indeed, some recent data suggest that vaccines might work quite well even if they do not stimulate CD4+ T cell responses. This grant application investigates several of the questions surrounding the important, but poorly-understood, cells.