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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

基本信息

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
项目类别：
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

项目摘要

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：长寿命记忆 CD8+ T 细胞的开发对于控制病毒至关重要感染，例如流感。促进记忆 CD8+ T 的细胞外因子的完整鉴定细胞将有利于更好地设计 CD8+ T 细胞诱导免疫和抗病毒疗法。值得注意的是，我们发现这些因素之一，细胞外 ATP (eATP) – 通过其受体 P2RX7 – 促进病毒特异性记忆 CD8+ T 细胞的生成和长期存活，均在循环系统中（中枢）记忆细胞 - TCM）和屏障组织（常驻记忆细胞 - TRM）中对全身病毒感染的反应。这些发现强调了“危险信号”eATP 在促进抗病毒治疗方面发挥着意想不到的作用免疫。然而，对于P2RX7如何促进记忆CD8+ T细胞的理解仍然存在差距长期生存。对于 TRM 池来说尤其如此，它在系统性和系统性的背景下都相关。和组织局部感染。在目标 1 中，我们将基于初步研究表明 P2RX7 记忆前体子集的上调有利于长寿命 TRM 细胞的发育。我们特别有兴趣了解 P2RX7 在免疫的早期阶段如何优先上调反应会影响 TRM 细胞在该时间窗口后很长时间的存活。在目标 2 中，我们建议解决 P2RX7 如何在流感感染的情况下表达可促进 TRM 细胞的寿命。我们的初步数据表明，尽管肺部的初始播种大部分独立于 P2RX7（并且 P2RX7 本身的表达很低），流感特异性肺 TRM 细胞在这种感染典型的数量衰减中幸存下来，表达高水平的 P2RX7，并且需要这个受体来维持。我们将进行实验来了解 (a) 的起源表达 P2RX7 的长寿命流感特异性肺 TRM 细胞，以及 (b) 如何操纵 P2RX7 表达及其潜在的上游调节促进肺 TRM 细胞更好的存活及其保护能力继发性流感挑战。总的来说，我们将检验以下假设：针对多种病毒感染， eATP 传感器 P2RX7 的表达选择记忆 CD8+ T 细胞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 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未来潜在的实验装置旨在提高记忆 CD8+ T 细胞对流感的保护能力，一种具有高度医学相关性的疾病。