Control of antiviral memory CD8+ T cell longevity by extracellular ATP sensing

项目概述：开发长寿命记忆性CD 8 + T细胞对于控制病毒感染至关重要。 感染，如流感。促进记忆的细胞外因子CD 8 + T的完全鉴定 细胞将有利于更好地设计CD 8 + T细胞诱导免疫和抗病毒治疗。值得注意的是， 他们发现，这些因子之一，细胞外ATP（eATP）-通过其受体P2 RX 7-促进 病毒特异性记忆性CD 8 + T细胞的产生和长期存活，无论是在循环中（中央 记忆细胞- TCM）和屏障组织（驻留记忆细胞- TRM）中响应系统性病毒感染。 这些发现强调了“危险信号”eATP在促进抗病毒治疗中的意想不到的作用。 免疫力然而，对于P2 RX 7如何促进记忆性CD 8 + T细胞的表达， 长期生存。这对于TRM池尤其如此，这在系统性和非系统性两个方面都是相关的。 和组织局部感染。在目标1中，我们将建立在初步研究的基础上，研究表明P2 RX 7 记忆前体亚类的上调有利于长寿命TRM细胞的发育。我们特别 感兴趣的是了解P2 RX 7在免疫的早期阶段如何优先上调， 应答在该时间窗之后很长时间影响TRM细胞存活。在目标2中，我们建议解决P2 RX 7 在流感感染的情况下，表达促进TRM细胞寿命。我们的初步数据表明， 尽管肺的初始接种主要不依赖于P2 RX 7（并且P2 RX 7本身的表达低）， 流感特异性肺TRM细胞在这种感染的典型数量衰减中存活，表达高水平的 P2 RX 7，并需要这种受体来维持。我们将通过实验来了解（a） 表达P2 RX 7的长寿命流感特异性肺TRM细胞，和（B）如何操纵P2 RX 7表达和其表达 潜在的上游调节促进肺TRM细胞更好的存活和它们对抗肿瘤的保护能力。 二次流感攻毒。总的来说，我们将测试的假设，在应对多种病毒感染， eATP传感器P2 RX 7的表达选择记忆性CD 8 + T细胞，以在屏障组织中长期存活。 这些研究将确定这种eATP传感器的动态调节如何促进记忆的寿命 CD 8 + T细胞在不同的感染和炎症环境中。它们还将作为概念验证， 潜在的未来实验设置，旨在提高记忆CD 8 + T细胞对流感的保护能力， 一种高度医学相关的疾病

Project summary: Development of long-lived memory CD8+ T cells is paramount for the control of viral infections, such as influenza. The complete identification of extracellular factors promoting memory CD8+ T cells will favor the better design of CD8+ T cell-inducing immunizations and antiviral therapies. Notably, we have found that one of these factors, extracellular ATP (eATP) – via its receptor P2RX7 - promotes the generation and long-term survival of virus-specific memory CD8+ T cells, both in the circulation (central memory cells – TCM) and in barrier tissues (resident memory cells – TRM) in response to systemic viral infection. These findings highlight an unanticipated role for the “danger signal” eATP for the promotion of antiviral immunity. However, there still are gaps on the understanding of how P2RX7 promotes memory CD8+ T cell long-term survival. This is especially true for the TRM pool, which is relevant both in the context of both systemic and tissue-localized infections. In Aim 1, we will build up on preliminary studies suggesting that P2RX7 upregulation in a subset of memory precursors favor the development of long-lived TRM cells. We are especially interested in understanding how preferential upregulation of P2RX7 at such an early stage of the immune response affects TRM cell survival long after this time window. In Aim 2, we propose to address how P2RX7 expression promotes TRM cell longevity in the context of influenza infection. Our preliminary data suggests that, despite initial seeding of the lung is mostly independent of P2RX7 (and expression of P2RX7 itself is low), influenza-specific lung TRM cells that survive the numerical decay typical of this infection express high levels of P2RX7, and need this receptor to maintain. We will perform experiments to understand (a) the origin of P2RX7-expressing long-lived flu-specific lung TRM cells, and (b) how manipulating P2RX7 expression and its potential upstream regulation promote better survival of lung TRM cells and their protective ability against secondary influenza challenge. Overall, we will test the hypothesis that, in response to multiple viral infections, expression of the eATP sensor P2RX7 selects memory CD8+ T cells for long-term survival in barrier tissues. These studies will establish how dynamic regulation of this eATP sensor promotes the longevity of memory CD8+ T cells in distinct infection and inflammatory contexts. They will also serve as a proof-of-concept for potential future experimental setups aiming to boost the protective ability of memory CD8+ T cells to influenza, a disease of high medical relevance.