Harnessing type I interferon to promote lung-resident memory CD4 T cell immunity against influenza

项目摘要 驻留在感染部位的记忆性CD 4 T细胞是免疫的关键协调。越来越清楚的 促进这种组织驻留记忆（TRM）细胞的关键信号与那些 支持常规记忆T细胞亚群的产生。描述优化CD 4 TRM生成的信号 重要的是提高疫苗诱导的针对病原体如甲型流感病毒（IAV）的免疫力， 单独的抗体不能提供持久的保护。我们的数据表明，I型干扰素（IFN）可以促进 独特的激活模块，优化抗病毒CD 4 T细胞效应子向TRM的转变， 通过转录因子T-bet进行编程，限制了细胞采用这种“前TRM”效应器的能力 状态这一建议将打破关键机制的能力，I型干扰素，以促进肺CD 4 TRM在IAV感染和鼻内接种的翻译模型中的作用。 在目的1中，我们将使用小鼠模型来区分I型IFN如何直接向CD 4 T细胞和间接向CD 4 T细胞传递信号。 通过调节炎症环境，影响细胞的功能和转录特性， 预TRM效应器，并最终塑造TRM景观。我们还将确定T-bet在多大程度上 CD 4 T细胞的表达影响IFN调节TRM引发的能力。在目标2中，我们将确定如何 IAV致敏的CD 4 T细胞通过信号转导和转录激活因子解释I型IFN信号 （STAT）分子，以及I型IFN的特异性STAT激活特征通过STAT分子改变的程度。 我们发现记忆命运待定时的动力学窗口该分析将用于优化策略， 通过增加I型IFN对应答性CD 4 T细胞的可用性来加强TRM。有效CD 4的标志 TRM应答是它们的快速激活，这导致在全身免疫应答之前控制病毒滴度 开始了。由于I型干扰素对初始CD 4 T细胞活化具有抑制作用，我们认为CD 4 T细胞的活化可能与IFN-γ的表达有关。 TRM不仅能在遇到抗原时逃避这种抑制作用， 干扰素作为急性“触发器”优化他们的回忆。在目标3中，我们将确定这种机制在多大程度上 操作，以及T-bet和TRM的特定STAT表达如何微调这种反应。 该提案将通过阐明I型IFN如何被利用来提供高影响力的机制数据， 改善CD 4 TRM的产生和回忆，与IAV和可能的其他呼吸道病原体相关。我们 长期目标是开发疫苗和治疗策略，结合这项研究的见解， 肺中持久和快速反应的细胞免疫。

Project Summary Memory CD4 T cells residing at sites of infection are key orchestrators of immunity. It is increasingly clear that key signals promoting such tissue-resident memory (TRM) cells do not overlap completely with those that support generation of conventional memory T cell subsets. Delineating signals that optimize CD4 TRM generation is important to improve vaccine-induced immunity against pathogens like influenza A virus (IAV) against which antibody alone cannot confer lasting protection. Our data indicates that type I interferons (IFN) can promote a unique activation module that optimizes the transition of anti-viral CD4 T cell effectors into TRM, and that Th1 programming, through the transcription factor T-bet, restricts the ability of cells to adopt this ‘pre-TRM’ effector state. This proposal will breakdown key mechanisms underlying the ability of type I IFN to promote lung CD4 TRM during IAV infection and in a translational model of intranasal vaccination. In Aim 1, we will use mouse models to differentiate how direct type I IFN signals to CD4 T cells, and indirect effects through modulating the inflammatory environment, impact the functional and transcriptional identity of pre-TRM effectors and ultimately shape the TRM landscape. We will also determine the extent to which T-bet expression by CD4 T cells effects the ability of I IFN to modulate TRM priming. In Aim 2, we will determine how IAV-primed CD4 T cells interpret type I IFN signals through signal transducer and activator of transcription (STAT) molecules, and the extent to which specific STAT activation signatures by type I IFN change through the kinetic window when we find memory fate to be determined. This analysis will be used to optimize strategies to boost TRM through increasing availability of type I IFN to responding CD4 T cells. A hallmark of effective CD4 TRM responses is their rapid activation which results in control of viral titers before systemic immune responses are initiated. As Type I IFNs have a suppressive impact on naive CD4 T cell activation, we propose that CD4 TRM are specialized to not only escape this suppressive impact during antigen encounter, but to harness type I IFN as an acute ‘trigger’ optimizing their recall. In Aim 3 we will determine the extent to which this mechanism operates, and how T-bet and specific STAT expression by TRM fine-tune this response. This proposal will provide high impact mechanistic data by elucidating how type I IFN can be harnessed to improve the generation and recall of CD4 TRM, with relevance to IAV and likely other respiratory pathogens. Our long-term goal is develop vaccine and therapeutic strategies incorporating insights from this research to improve durable and rapidly responsive cellular immunity in the lung.