Functional Analyses of Antiviral CD4+ T Cell Responses

保护性免疫，无论是由感染或接种疫苗诱导的，都依赖于记忆的产生 数量充足、质量充足的B&T细胞。这一进程的成功在很大程度上 依赖于由CD4+T细胞提供的“帮助”。CD4+T细胞在协调人类免疫功能中起着核心作用 适应免疫反应，但调节其丰度的机制， 反复抗原接触的重要性以及它们为CD8+T细胞ALL提供帮助的方式 仍然不确定。这项应用的总体目标是：(I)继续我们对CD4+T细胞如何 体内的数量和质量是由干扰素调节的，以及体内与干扰素的接触如何影响它们 持久性病毒抗原(目标1和2)；和(Ii)研究CD4+T细胞如何提供帮助，即 发育良好的抗病毒CD8+T细胞记忆所必需的(目标3和4)。 目的1.确定直接干扰素信号如何对原生生物的丰度产生深刻影响 和记忆中的CD4+T细胞。我们已经证明，可以直接对干扰素产生反应的CD4+T细胞是100- 在内存池中折叠更丰富的内存。我们将确定干扰素的作用何时发挥； 结果是基因表达的变化；以及哪些细胞产生了这种重要的细胞因子。 目的2.评价延长MHC-II类抗原提呈时间对CD4+T细胞数量的影响 和质量。众所周知，在慢性感染期间，持久性抗原可以显著改变 T细胞反应。然而，抗原持久性的问题在模型中定义得很不清楚。 急性病毒感染。我们发现MHC II类在急性病毒感染后数周内呈现病毒抗原。 感染。我们将测量持久性抗原对CD4+T细胞功能的影响。抗原有没有- 推动干扰素的产生塑造了CD4+T细胞的反应？ 目的3.探讨病毒特异性和非特异性CD4+T细胞的免疫功能。我的实验室 是首批表明CD4+T细胞在建立CD8+T细胞记忆中起关键作用的人之一 在急性病毒感染后，一项观察得到了一些人的证实和推广 实验室。令人惊讶的是，CD4+T细胞似乎能够帮助CD8+T细胞在非特异性 (“非同源”)时尚。我们将比较针对一种病毒的CD4+T细胞的帮助 表位，与不能识别病毒的CD4+T细胞的帮助。 目的4.确定干扰素是否为CD4+T细胞辅助性免疫反应的关键介质。最终的目标是把两个人聚集在一起 线索：(I)良好的CD8+T细胞记忆的形成需要CD4+T细胞的帮助 以及(Ii)我们最近发现，干扰素对CD8+T细胞记忆的发展至关重要。力所能及 干扰素是CD4+T细胞帮助CD8+T细胞记忆发展的“纽带”吗？的角色是 干扰素对特异性和非特异性的CD4+辅助T细胞是否相同？

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 the 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?