Mucosal T cell memory to pathogens

粘膜T细胞对病原体的记忆

• 批准号: 10251871
• 负责人: DAVID MASOPUST
• 金额: $ 47.75万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10251871
• 关键词: Address; Adoptive Cell Transfers; Antigens; Award; Bioinformatics; Biology; Blood; Blood Circulation; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancerous; Cell Aging; Cell physiology; Cells; Cellular biology; Cessation of life; Chronic; Clonal Expansion; Computational Biology; Consumption; Data; Disease; Evolution; Exposure to; Gene Expression Profile; Generations; Genes; Grant; Hand; Homing; Human; Immune system; Immunity; Immunobiology; Immunologic Surveillance; Immunology; Immunotherapy; Integrins; Journals; Knowledge; Life; Light; Location; Lymphocyte; Malignant Neoplasms; Medical; Memory; Modeling; Molecular; Mucous Membrane; Mus; Nature; Operative Surgical Procedures; Paper; Parabiosis; Population; Progress Reports; Property; Publications; Regulation; Resources; Role; Running; Secondary Immunization; Study Subject; Surveys; T cell differentiation; T cell therapy; T memory cell; T-Lymphocyte; Testing; Time; Tissues; Vaccination; Virus Diseases; Work; antimicrobial; bench to bedside; cell motility; chemokine; chronic infection; cohort; comparative; exhaust; exhaustion; experimental study; fMet-Leu-Phe receptor; meetings; migration; neglect; overexpression; pathogen; population based; programmed cell death protein 1; programs; residence; senescence; stem; tool; transcriptome sequencing; tumor microenvironment; vaccine trial

PROJECT SUMMARY Iterative T cell stimulation can result in senescence, exhaustion, or death (SED) as observed during chronic viral infections, certain heterologous prime boost (HPB) vaccination studies, or cancer. Knowing whether there are axiomatic limits to T cell clonal expansion is a critical gap in knowledge relevant for immunotherapy of diverse diseases as well as fundamental understanding of immunobiology. In pilot experiments that began >8y ago, we identified a stimulation strategy revealing that memory CD8 T populations are essentially infinitely expansible, our oldest population having gone through 38 booster immunizations over 3200 days (longer than any mouse lives) and effectively producing >1030 progeny. We hypothesize that this proof-of-principle, extreme-of-nature experiment reveals fundamental T cell biology highly relevant to our understanding of the immune system and provides unexpected observations that could be exploited for medically relevant purposes. We will leverage this unique resource (ISTCs, iteratively stimulated T cells) to explore the consequences of iterative stimulation on T cell biology. We will address the rules for avoiding SED despite repeated stimulation, the relevance of ISTCs expressing exhaustion-associated genes without appearing functionally exhausted, and the mechanisms by which ISTCs durably retain the unique effector-like property of circulation between blood and mucosal tissues. Aim 1. To define the regulation and evolution of the ISTC differentiation program. We will 1) define the evolution of ISTCs at the single cell level using bioinformatic and computational biology approaches, 2) define rules for avoiding T cell SED by modifying the parameters of our stimulation strategy, and 3) contrast ISTCs from exhausted T cells (Tex) on a molecular level by comparing gene expression patterns of Tex and consecutive generations of ISTCs. We will test the hypotheses that 1) everlasting proliferative capacity depends on avoiding terminal differentiation of a ‘stem’ population, 2) excessive division over a short period of time promotes terminal differentiation, and 3) despite sharing key features with exhausted cells, functional ISTCs will reveal discrete patterns of gene expression thus refining the molecular definition of exhaustion. Aim 2. To define ISTC recirculation properties, mechanisms of immunosurveillance, and antimicrobial functions. ISTCs represent a unique opportunity to interrogate mechanisms of nonlymphoid tissue recirculation. We will 1) define the migration properties of ISTCs using parabiosis surgeries, photoactivatable mouse lines, and perturbing homing molecules, 2) assess the protective potential of ISTCs in a LM-N challenge model, and 3) extend these findings to ‘dirty’ mice (mice which have been iteratively exposed to natural pathogens) and humans. We will test the hypotheses that 1) ISTCs recirculate through NLTs, 2) ISTCs can protect against pathogen challenge, and 3) ISTCs can be identified in ‘dirty’ mice and humans.

项目摘要 反复的T细胞刺激可导致衰老、衰竭或死亡（SED），如在慢性病毒感染期间观察到的。 感染、某些异源初免加强（HPB）疫苗接种研究或癌症。知道是否有 对T细胞克隆扩增的公理限制是与多种免疫疗法相关的知识中的关键空白。 疾病以及免疫生物学的基本理解。在8年前开始的试点实验中，我们 确定了一种刺激策略，揭示了记忆CD8 T细胞群基本上是无限扩展的， 我们最老的种群在3200天内经历了38次加强免疫（比任何老鼠都长 存活）并且有效地产生> 1030个后代。我们假设这个原理性的证明， 实验揭示了基本的T细胞生物学与我们对免疫系统的理解高度相关， 提供了可用于医学相关目的的意外观察结果。我们会利用这个 独特的资源（ISTC，迭代刺激的T细胞），以探索迭代刺激对T细胞的影响。 细胞生物学我们将讨论避免SED的规则，尽管反复刺激，ISTC的相关性， 表达衰竭相关基因而不出现功能衰竭，以及通过 所述ISTC持久地保持血液和粘膜组织之间循环的独特效应子样性质。 目标1.明确ISTC分化程序的调节和演变。我们将1）定义 使用生物信息学和计算生物学方法在单细胞水平上进化ISTC，2）定义 通过修改我们的刺激策略的参数来避免T细胞SED的规则，以及3）将ISTC与 在分子水平上通过比较Tex和连续的Tex的基因表达模式， 一代又一代的ISTC我们将检验以下假设：1）持久的增殖能力取决于避免 "茎"群体的末端分化，2）短时间内的过度分裂促进末端分化， 分化，以及3）尽管与疲惫的细胞具有共同的关键特征，但功能性ISTC将揭示离散的 基因表达的模式，从而完善了衰竭的分子定义。 目标二。明确ISTC的再循环特性、免疫监视机制， 抗菌功能ISTC代表了一个独特的机会，询问非淋巴细胞的机制， 组织再循环我们将1）使用共生手术定义ISTC的迁移特性， 光活化小鼠系和干扰归巢分子，2）评估ISTC在小鼠中的保护潜力， LM-N攻击模型，以及3）将这些发现扩展到"脏"小鼠（已经反复暴露的小鼠 自然病原体）和人类。我们将检验以下假设：1）ISTC通过NLT再循环，2）ISTC 可以保护免受病原体攻击，和3）ISTC可以在“脏”小鼠和人类中鉴定。