Role of the microenvironment in regulating early stages of thymic involution and central tolerance

微环境在调节胸腺复旧和中枢耐受早期阶段的作用

• 批准号: 10553994
• 负责人: Lauren Ilyse Richie EHRLICH
• 金额: $ 79.09万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-15 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10553994
• 关键词: Adult; Age; Aging; Antigen-Presenting Cells; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmunity; Avidity; Biological Assay; Bone Marrow; Cell Aging; Cell Compartmentation; Cell physiology; Cells; Cellularity; Data; Data Set; Defect; Development; Frequencies; Gene Expression Profiling; Generations; Genetic; Goals; Health; Hematopoiesis; Hematopoietic; Human; Image; Immune response; Immunity; Impairment; Incidence; Ligands; Longevity; Lymphoid; Lymphopoiesis; Maintenance; Malignant Neoplasms; Mediator; Molecular; Morbidity - disease rate; Mus; Output; Peripheral; Predisposition; Process; Production; Regulatory T-Lymphocyte; Rejuvenation; Role; Sex Bias; Signal Transduction; Slice; Stromal Cells; Structure; T cell response; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Thymus Gland; Tumor Antigens; Vaccines; central tolerance; fetal; functional restoration; imaging approach; immune function; improved; middle age; mouse model; notch protein; pathogen; prevent; progenitor; programs; response; stem cells; thymocyte; two-photon

ABSTRACT-Project 2 During the process of age-associated thymus involution, T cell output progressively declines, contributing to a reduction in naive T cells in older humans and mice. The resultant decline in new T-cell responses to pathogens, vaccines, and cancers, leads to compromised immunity and increased morbidity with age. Thus, it is important to elucidate mechanisms underlying reduced thymic function in order to improve human health throughout the lifespan. In the past Project period, we found that early T-cell progenitors (ETPs), which give rise to all downstream thymocyte subsets, decline in numbers surprisingly early, by 3 months (mo) of age. ETP cellularity remains proportional to downstream thymocyte subsets at all ages, indicating the early decline in ETPs sets the stage for diminished thymopoiesis during thymic involution. Because ETPs are the direct progeny of circulating thymic seeding progenitors (TSPs), we anticipated a decline in the number of functional TSP niches by 3mo of age. However, our data reveal that the available TSP niches do not decline through at least 12mo of age, raising the question of what mechanisms underlie the early reduction in ETPs. Our preliminary data suggest that changes in the BM and thymus microenvironments contribute to the early loss in ETPs. Although the underlying mechanisms are not yet resolved, preliminary data suggest diminished NOTCH signaling in BM lymphoid progenitors and thymic ETPs contribute. Thus, we will use genetic mouse models and advanced imaging approaches to test if reduced expression of Notch ligands, and/or changes in other signals identified through additional single-cell transcriptional profiling (Core B), are responsible for the early decline in lymphoid progenitors in the BM (Aim 1) and ETPs in the thymus (Aim 2), and whether comparable mechanisms impact the aging human thymus (Core C). We will also test if restoring NOTCH signaling rescues cellularity of BM lymphoid progenitors, ETPs and thymocytes, and downstream T cell function in aging mice (P3 and Core D). Changes in the cellular composition and organization of the thymic microenvironment during involution may impact not only the quantity, but also the quality of developing T cells with age. During the previous Project period, we found that by middle age, the thymus becomes impaired in its ability to support central tolerance through both negative selection and regulatory T cell generation, particularly in response to low avidity self- antigens. New onset autoimmunity also peaks at middle age in humans, suggesting a role for impaired central tolerance. Thus, we will analyze current single-cell transcriptional profiling datasets from P2 and P1 (Core B) and perform live 2-photon imaging and thymic slice assays to identify age-associated changes in the mouse and human (Core C) thymic microenvironments that impair central tolerance and increase autoimmune susceptibility by middle-age (Aim 3). P2 is tightly integrated with P1, P3, and the Cores. P2 results will be integral to achieving the overall Program goals of elucidating mechanisms underlying age-associated defects in T-cell production and selection and devising therapeutic strategies to restore functional T cell output and immunity with age.

抽象项目2 在与年龄相关的胸腺相关过程中，T细胞的输出逐渐下降，有助于 年龄较大的人和小鼠幼稚T细胞的降低。新的T细胞对 病原体，疫苗和癌症会导致免疫力受损，并随着年龄的增长而增加。因此，它 对于阐明降低胸腺功能以改善人类健康的机制很重要 在整个生命周期中。在过去的项目期间，我们发现引起的早期T细胞祖细胞（ETP） 对于所有下游胸腺群，数量令人惊讶地减少了3个月（MO）年龄。 ETP 细胞性在所有年龄段与下游胸腺群成正比，表明ETP的早期下降 为胸腺涉及期间胸腺胞菌减少的阶段设定了阶段。因为ETP是直接的后代 循环的胸腺播种祖细胞（TSP），我们预计功能性TSP壁ch的数量会下降 到3mo的年龄。但是，我们的数据表明，可用的TSP壁ches不会通过至少12MO的下降 年龄，提出了一种问题，即哪些机制是ETP早期减少的基础。我们的初步数据暗示 BM和胸腺微环境的变化会导致ETP的早期损失。虽然 潜在机制尚未解决，初步数据表明BM中的Notch信号降低 淋巴样祖细胞和胸腺ETP贡献。因此，我们将使用遗传鼠标模型和高级 成像方法以测试减少缺口配体的表达和/或确定的其他信号的变化 通过其他单细胞转录分析（Core B），淋巴早期下降是原因 BM中的祖细胞（AIM 1）和胸腺中的ETP（AIM 2），以及可比机制是否影响 衰老的人胸腺（核心C）。我们还将测试是否还原Notch信号挽救了BM的细胞性 淋巴样祖细胞，ETP和胸腺细胞以及衰老小鼠的下游T细胞功能（P3和Core D）。 乳腺微环境的细胞组成和组织的变化 不仅可能影响数量，而且会影响随着年龄的增长而发展的T细胞的质量。在上一个项目中 时期，我们发现，到中年，胸腺支持中央公差的能力受损 通过负选择和调节性T细胞的产生，特别是为了响应低流动自我 抗原。新的发病自身免疫也在中年的中年达到顶峰，这表明中央受损的角色 宽容。因此，我们将分析来自P2和P1的当前单细胞转录分析数据集（Core B） 并进行活2光子成像和胸切片测定法，以识别小鼠与年龄相关的变化 人（核心C）胸腺微环境会损害中央耐受性并增加自身免疫性的易感性 在中年（目标3）。 P2与P1，P3和核心紧密整合。 P2结果将是成就不可或缺的 阐明T细胞生产中与年龄相关的缺陷的基础机制的总体计划目标 选择和设计治疗策略，以随着年龄的增长而恢复功能性T细胞输出和免疫力。