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

通过细胞外 ATP 传感控制抗病毒记忆 CD8 T 细胞寿命

• 批准号: 10657776
• 负责人: Henrique Borges da Silva
• 金额: $ 47.37万
• 依托单位: MAYO CLINIC ARIZONA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10657776
• 关键词: Address; Affect; Antibodies; Antiviral Therapy; CD8-Positive T-Lymphocytes; CD8B1 gene; CRISPR/Cas technology; Cell Death; Cell Survival; Cells; Circulation; Complement; Complex; Cues; Data; Development; Disease; Effector Cell; Focal Infection; Future; Generations; Genetic; Goals; Homeostasis; Immune response; Immunity; Immunization; Infection; Inflammation; Inflammatory; Influenza; Knock-out; Knowledge; Longevity; Lung; Maps; Mediating; Medical; Memory; Natural Immunity; Pathway interactions; Persons; Population; Regulation; Reporter; Reporting; Role; Route; Signal Transduction; Structure of parenchyma of lung; Systemic infection; Testing; Time; Tissues; United States; Up-Regulation; Vaccines; Viral; Virus; Virus Diseases; adaptive immunity; antiviral immunity; cytotoxic CD8 T cells; design; experimental study; extracellular; flu; imprint; influenza infection; influenza virus strain; influenzavirus; interest; lung injury; overexpression; receptor; response; secondary lymphoid organ; sensor; tool

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.

项目摘要：长寿记忆CD8+ T细胞的发展对于控制病毒至关重要 感染，例如影响力。促进记忆CD8+ T的细胞外因子的完整鉴定 细胞将有利于CD8+ T细胞诱导免疫抑制和抗病毒疗法的更好设计。值得注意的是，我们 发现这些因素之一是细胞外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都在循环中（中心 记忆细胞 - TCM）和屏障组织（居民记忆细胞 - TRM），响应全身病毒感染。 这些发现突出了“危险信号” EATP的意外作用，以促进抗病毒 免疫。但是，关于P2RX7如何促进内存CD8+ T细胞的理解仍然存在差距 长期生存。对于TRM池尤其如此，这在两个系统中都相关 和组织关闭的感染。在AIM 1中，我们将基于初步研究，表明P2RX7 记忆前体中的上调有利于长寿命TRM细胞的发展。我们尤其是 有兴趣了解在免疫的早期阶段如何首选P2RX7的上调 响应在此时间窗口后很长时间影响TRM细胞的存活。在AIM 2中，我们建议解决P2RX7的方式 在影响力感染的背景下，表达促进了TRM细胞寿命。我们的初步数据表明， 尽管肺的初始播种主要独立于P2RX7（P2RX7本身的表达很低），但 在这种感染的典型数值衰减中生存的影响力特异性肺TRM细胞表达高水平的高水平 P2RX7，需要该受体维护。我们将执行实验以了解（a） 表达P2RX7的长期流感特异性肺TRM细胞，以及（b）如何操纵P2RX7表达及其如何 潜在的上游调节可促进肺部TRM细胞的更好生存及其对抗的保护能力 次要影响力挑战。总体而言，我们将检验以下假设：响应多种病毒感染， EATP传感器P2RX7的表达选择记忆CD8+ T细胞以在屏障组织中长期存活。 这些研究将确定该EATP传感器的动态调节如何促进记忆的寿命 在不同的感染和炎症环境中的CD8+ T细胞。他们还将作为概念证明 潜在的未来实验设置旨在提高记忆CD8+ T细胞的保护能力，以影响ZA， 高医学相关性的疾病。