Functional Analyses of Antiviral CD4+ T Cell Responses

保护性免疫，无论是通过感染还是通过接种疫苗诱导，都依赖于记忆的产生 足够数量和足够质量的B和T细胞。这个过程的成功， 依赖于CD 4 + T细胞提供的“帮助”。CD 4 + T细胞在协调免疫应答中起着核心作用。 适应性免疫反应，但其丰度的调节机制， 反复抗原接触的重要性，以及它们为CD 8 + T细胞提供帮助的方式， 仍然不确定。本申请的总体目标是（i）继续研究CD 4 + T细胞如何与CD 4 + T细胞结合。 数量和质量在体内由IFN？调节，以及它们如何受到体内接触IFN？的影响。 持久性病毒抗原（目的1和2）;和（ii）研究CD 4 + T细胞如何提供帮助， 这是开发良好的抗病毒CD 8 + T细胞记忆所需的（目的3和4）。 目标1.为了确定直接的IFN？信号传导如何对原发性肿瘤的丰度产生深远的影响， 和记忆性CD 4 + T细胞。我们已经证明，可以直接对IFN？产生反应的CD 4 + T细胞是100- 在内存池中更加丰富。我们将确定IFN的效果何时发挥;什么 基因表达的变化，以及哪些细胞产生这种重要的细胞因子。 目标二。目的：探讨MHC Ⅱ类抗原递呈时间延长对CD 4 + T细胞数量的影响 和质量众所周知，在慢性感染期间，持续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免疫缺陷模型中没有很好地定义。 急性病毒感染我们已经发现，急性病毒感染后，MHCII类呈递病毒抗原数周， 感染我们将测量持续抗原对CD 4 + T细胞功能的影响。抗原- 驱动IFN？的产生塑造了CD 4 + T细胞反应？ 目标3.研究病毒特异性和非特异性CD 4 + T细胞提供的帮助。我的实验室 是最早发现CD 4 + T细胞在建立CD 8 + T细胞记忆中起关键作用的人之一 在急性病毒感染后，一个观察结果已经被一些 labs.令人惊讶的是，CD 4 + T细胞似乎能够在非特异性免疫应答中为CD 8 + T细胞提供帮助。 （“noncognate”）时尚。我们将比较CD 4 + T细胞对病毒特异性的帮助， 表位，在无法识别病毒的CD 4 + T细胞的帮助下。 目标4。确定IFN是否是CD 4 + T细胞帮助的关键介质。最后的目标是将两个 线索：（i）事实上，CD 4 + T细胞的帮助是需要良好的CD 8 + T细胞记忆的发展 以及（ii）我们最近发现IFN对CD 8 + T细胞记忆的发展至关重要。可能 IFN是CD 4 + T细胞帮助CD 8 + T细胞记忆发展的“纽带”吗？的作用是 IFN对特异性和非特异性CD 4+辅助T细胞相同吗？

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?