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

项目摘要：开发长寿命记忆CD8+T细胞对控制病毒至关重要 感染，如流感。促进记忆CD8+T细胞外因子的完整鉴定 细胞将有利于CD8+T细胞诱导免疫和抗病毒治疗的更好设计。值得注意的是，我们 已发现其中一种因子，细胞外ATP(EATP)--通过其受体P2RX7--促进 病毒特异性记忆CD8+T细胞的产生和长期存活，两者都在循环中(中央 记忆细胞)和屏障组织(常驻记忆细胞-TRM)对全身病毒感染的反应。 这些发现突显了“危险信号”eATP在促进抗病毒方面的意外作用。 豁免权。然而，关于P2RX7如何促进记忆性CD8+T细胞的研究还存在空白 长期生存。对于TRM池来说尤其如此，这在两个系统的背景下都是相关的 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，表明P2RX7 部分记忆前体细胞的上调有利于长期存活的TRM细胞的发展。我们特别是 有兴趣了解在免疫的早期阶段P2RX7是如何优先上调的 反应会影响TRM细胞在这一时间窗口后很长时间的存活。在目标2中，我们建议解决P2RX7如何 在流感感染的背景下，表达可促进TRM细胞的寿命。我们的初步数据表明， 尽管肺的初始播种在很大程度上独立于P2RX7(并且P2RX7本身的表达很低)， 在这种感染的典型数量衰退中幸存下来的流感特异性肺TRM细胞表达高水平的 P2RX7，并需要这种受体来维持。我们将进行实验以了解(A)的起源 表达长寿命流感特异性肺TRM细胞的P2RX7，以及(B)如何调控P2RX7的表达及其 潜在的上游调控促进肺TRM细胞更好的存活及其保护能力 二次流感挑战。总体而言，我们将测试这一假设，即在应对多种病毒感染时， EATP传感器P2RX7的表达选择了记忆CD8+T细胞，以便在屏障组织中长期存活。 这些研究将确定eATP传感器的动态调节如何促进记忆的寿命 CD8+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，用于 未来可能会有旨在增强记忆CD8+T细胞对流感的保护能力的实验装置， 一种具有高度医学意义的疾病。

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.