Mechanisms of T Cell Memory Quiescence

T 细胞记忆静止机制

• 批准号: 10173470
• 负责人: Surojit Sarkar
• 金额: $ 33.85万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10173470
• 关键词: 2019-nCoV; Acquired Immunodeficiency Syndrome; Address; Administrative Supplement; Antibodies; Antigens; Area; Award; B-Lymphocytes; Bacterial Infections; Biological; CD28 gene; COVID-19; COVID-19 pandemic; CTLA4 gene; CTLA4-Ig; Cells; Cellular Immunity; Centers for Disease Control and Prevention (U.S.); Childhood; Clinical; Clinical Trials; Communicable Diseases; Consensus; Development; Disease Outbreaks; Drug usage; Economic Burden; Economics; Endemic Diseases; Engineering; Epidemic; Etiology; Evaluation; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Exposure to; FDA approved; Foundations; Future; General Population; Glycoproteins; Goals; Growth; Healthcare; Hepatitis C virus; Herd Immunity; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunologic Memory; Lead; Location; Longevity; Lung; Lymphoid Tissue; Malaria; Mediating; Memory; Metabolic; Modeling; Molecular; Normalcy; Nucleoproteins; Outcome; Parents; Pharmaceutical Preparations; Phase; Play; Property; Proteins; Public Health; Recovery; Regulatory T-Lymphocyte; Research; Rest; Rheumatoid Arthritis; Role; Severe Acute Respiratory Syndrome; Signal Transduction; Speed; Structural Protein; T memory cell; T-Lymphocyte; Time; Transgenic Mice; Travel; Tuberculosis; United States National Institutes of Health; Vaccination; Vaccine Design; Vaccines; Vaccinia virus; Viral; Virulent; Virus Diseases; Work; antigen-specific T cells; antiviral immunity; base; clinical development; clinical translation; drug testing; expression vector; fight against; immunomodulatory strategy; inhibitor/antagonist; mouse model; multimodality; neutralizing antibody; pandemic disease; pathogen; pre-clinical; programs; protective efficacy; protein expression; public health relevance; repository; response; service providers; tool; vaccine candidate; vaccine-induced immunity; vector

ABSTRACT (COVID-19 SUPPLEMENTAL RESEARCH) During fast-spreading disease outbreaks (such as the present COVID-19 pandemic), quick induction of herd immunity through vaccination is critical. Currently there are many SARS-CoV2 candidate vaccines in various stages of clinical development, aimed at inducing robust multimodal protective immunity comprising both long-lived antibody and memory T cells. However, we have little control over how quickly protective immunity may be established following immunization. At the very minimum, vaccine-induced T cells require a period of ~20-30 days of antigenic rest after initial immunization to effectively downregulate their effector program and convert into quiescent, functionally potent, long-lived memory cells poised at portals of pathogen entry. If vaccine-induced T cells are re-exposed to antigen during this mandatory rest period – as might occur in case of exposure to virulent pathogen during an outbreak – the quantity, quality and overall protective efficacy of immune memory are significantly jeopardized. Hence, shortening the window of immune memory development is a key goal during vaccination, and is of high significance during pandemics to establish accelerated protection in frontline healthcare and essential service providers, and speed up herd immunity in the general population for expedited return to normalcy and economic growth. In this administrative supplement, we will evaluate candidate immunomodulatory strategies to accelerate and enhance vaccine-induced protective T cell memory to SARS-CoV2 by facilitating Treg-aided effector-to- memory conversion. This work is based on our studies establishing a critical role of Tregs in promoting effector-to-memory conversion through CTLA4, an inhibitory molecule most highly expressed on Tregs (amongst all immune cells) (Immunity, 2015). Importantly, soluble CTLA4 administered in trans, is alone able to fully supplement the function of Tregs in memory differentiation, and accelerates the formation of protective anti-viral immunity by promoting the metabolic switch necessary for effector-to-memory conversion. These proof-of-concept studies in models of viral immunity (conducted under the aegis of past R21, and parent R01 awards) lay a strong foundation for enhancing SARS-CoV2-specific immune memory following immunization with candidate SARS-CoV2 vaccine in preclinical murine model. These studies represent a natural translational extension of the parent R01 focused on mechanistic and molecular details of Treg-dependent memory enhancement through CTLA4 in model viral infections. Importantly, CTLA4-Ig is FDA-approved Phase III drug – ready for clinical translation. Therefore, immediate impact on our ability to quickly establish herd immunity against SARS-CoV2 is expected. In addition to addressing the current COVID-19 exigency, these studies are also relevant to other pandemics and situations of urgent vaccination of our defense troops for quick deployment to disease endemic areas.

摘要（COVID-19补充研究） 在快速传播的疾病爆发期间（如目前的COVID-19大流行）， 通过疫苗接种实现群体免疫至关重要。目前有许多SARS-CoV 2候选疫苗， 临床开发的各个阶段，旨在诱导稳健的多模式保护性免疫，包括 长寿命抗体和记忆T细胞。然而，我们几乎无法控制保护性的 免疫可以在免疫后建立。至少，疫苗诱导的T细胞需要 初始免疫后约20-30天的抗原休止期，以有效下调其效应子 编程并转化为静止的、功能强大的、长寿的记忆细胞， 入境如果疫苗诱导的T细胞在这一强制性休息期内重新暴露于抗原， 在暴发期间暴露于有毒病原体的情况下-数量、质量和总体保护 免疫记忆的功效受到显著危害。因此，缩短免疫记忆的窗口 发育是疫苗接种期间的一个关键目标，在大流行期间， 加速一线医疗保健和基本服务提供者的保护，并加速群体免疫， 加快恢复正常和经济增长。 在本行政补充中，我们将评估候选免疫调节策略，以加速和 通过促进Treg辅助的效应子-受体结合，增强疫苗诱导的保护性T细胞对SARS-CoV 2的记忆， 记忆转换这项工作是基于我们的研究，建立了一个关键作用，TdR在促进 通过CTLA 4（一种在Tcells上表达最高的抑制分子）的效应器-记忆转换 （在所有免疫细胞中）（Immunity，2015）。重要的是，反式施用的可溶性CTLA 4能够单独地 充分补充TGFAP在记忆分化中的作用，促进保护性记忆的形成， 通过促进效应器到记忆转换所必需的代谢转换来实现抗病毒免疫。这些 病毒免疫模型的概念验证研究（在过去的R21和母体R 01的支持下进行 为增强SARS-CoV 2特异性免疫记忆奠定了坚实的基础 与候选SARS-CoV 2疫苗在临床前小鼠模型中的作用。这些研究代表了一种自然的 亲本R 01的翻译延伸集中在Treg依赖性的转录调控的机制和分子细节上。 在模型病毒感染中通过CTLA 4增强记忆。重要的是，CTLA 4-IG是FDA批准的阶段 III药物-准备用于临床转化。因此，立即影响我们迅速建立畜群的能力 对SARS-CoV 2的免疫力。除了应对当前的COVID-19紧急情况外， 研究还涉及其他流行病和我们国防部队紧急接种疫苗的情况， 快速部署到疾病流行地区。