Identifying Mechanisms Governing T Cell Diversity

识别 T 细胞多样性的调控机制

• 批准号: 9350465
• 负责人: Jaehyuk Choi
• 金额: $ 237万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9350465
• 关键词: Adaptive Immune System; Benign; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cells; Characteristics; Clone Cells; Complex; Crowding; Cutaneous; Cutaneous Lymphoma; Data; Disease; Ensure; Health; Homeostasis; Homing; Human; Immune system; Immunologics; Individual; Longevity; Lymphopenia; Maintenance; Malignant - descriptor; Memory; Non-Hodgkin' s Lymphoma; Pathologic; Patients; Phenotype; Population; Resistance; Resolution; Signal Transduction; T-Cell Lymphoma; T-Cell Receptor; T-Lymphocyte; Thymus Gland; Time; Tumor Immunity; Viral; aged; base; cohort; emerging adult; high dimensionality; innovation; insight; neoplastic cell; pathogen; trend

PROJECT SUMMARY The hallmarks of the adaptive immune system are diversity and memory. A diverse T cell repertoire is critical to ensure an effective defense against a near infinite number of potential viral, fungal, and bacterial pathogens. T cell diversity is generated in the thymus. Due to imprecise T cell receptor assembly, over 108 T cell clones are produced in the thymus, each expressing a unique T cell receptor. During early adulthood, the thymus involutes. Therefore, to maintain a healthy immune system, T cell diversity has to be sustained in the immunological periphery. Maintenance of T cell diversity requires fine tuning because small perturbations in the T cell pool can have dramatic effects over time on T cell diversity. Each clone must be supported by positive homeostatic signals that enable survival over decades. At the same time, each clone must not overproliferate. Because the immunological space appears to be fixed, overexpansion of individual T cell clones can potentially crowd out its neighbors. Despite the fundamental importance of T cell homeostasis to human health and disease, we lack mechanistic insight into how T cell diversity is maintained. There are two important barriers to progress. For one, human studies have often focused on relatively small, unrelated cohorts of phenotypically heterogeneous aged individuals. Secondly, the study of a complex heterogeneous cell population requires assays with single cell resolution. To overcome these barriers, we propose to study a phenotypically similar cohort of human outliers who have profound alterations in their T cell repertoire, namely patients with cutaneous T cell lymphoma (CTCL). CTCL is an incurable non-Hodgkin lymphoma of the skin- homing CD4+ T cell. Patients with advanced leukemic CTCL invariably develop overproliferation of the malignant T cell clone and profound losses of the benign, untransformed CD4+ and CD8+ T cells. This lymphopenia is a characteristic feature of disease, develops in a stage-dependent manner, and is inevitable in patients with Stage IV disease. Presumably, the loss of normal T cells benefits the tumor cells by inhibiting anti-tumor immunity. Emerging data suggest that these two antiparallel trends occur due to pathological alterations in the homeostatic signals that keep clones alive and the homeostatic signals that keep clones from overcrowding the population. We hypothesize that the CTCL tumor cells have hyperactivation of the positive homeostatic signals and resistance to the negative homeostatic signals. Conversely, the disappearing, benign T cells in CTCL patients are relatively resistant to the positive homeostatic signals and highly sensitive to the negative homeostatic signals produced by CTCL cells. To elucidate disease mechanisms, we will use high- dimension discovery based approaches to identify and functionally validate high priority molecules that govern T cell homeostasis. We believe that successful completion of this proposal will identify important homeostatic signaling mechanisms that are fundamentally important for T cell homeostasis in health and in other diseases.

项目摘要 自适应免疫系统的标志是多样性和记忆。多样化的T细胞库对于 确保对几乎无限数量的潜在病毒，真菌和细菌病原体的有效防御。 t 细胞多样性是在胸腺中产生的。由于不精确的T细胞受体组件，超过108个T细胞克隆是 在胸腺中产生，每种表达独特的T细胞受体。在成年初期，胸腺 统治。因此，要维持健康的免疫系统，T细胞多样性必须在 免疫学周围。 T细胞多样性的维护需要微调，因为小扰动 T细胞池会随着时间的流逝而对T细胞多样性产生巨大影响。每个克隆必须由 积极的稳态信号可以使数十年来生存。同时，每个克隆都不能 过度增殖。因为免疫空间似乎是固定的，所以单个T细胞过度膨胀 克隆可能会挤出邻居。尽管T细胞稳态对 人类健康和疾病，我们缺乏对如何保持T细胞多样性的机械洞察力。有两个 进步的重要障碍。首先，人类研究通常集中于相对较小的无关 表型异构老年人的同类。其次，对复杂异质的研究 细胞种群需要单细胞分辨率的测定。为了克服这些障碍，我们建议研究 在表型上相似的人类异常值，他们的T细胞库有深刻的变化，即 皮肤T细胞淋巴瘤（CTCL）患者。 CTCL是皮肤无法治愈的非霍奇金淋巴瘤 归居CD4+ T细胞。患有晚期白血病CTCL的患者总是会出现过度增殖 恶性T细胞克隆和良性，未转化的CD4+和CD8+ T细胞的深刻损失。这 淋巴细胞减少是疾病的特征，以阶段依赖性的方式发展，不可避免 患有IV期疾病的患者。据推测，正常T细胞的丧失通过抑制来使肿瘤细胞受益 抗肿瘤免疫。新兴数据表明，这两种反平行趋势是由于病理而发生的 稳态信号的改变，使克隆保持活力和使克隆避免克隆的稳态信号 人口过度拥挤。我们假设CTCL肿瘤细胞具有阳性的过度激活 稳态信号和对负稳态信号的阻力。相反，消失，良性 CTCL患者中的T细胞对阳性稳态信号具有相对抗性，并且对 CTCL细胞产生的负稳态信号。为了阐明疾病机制，我们将使用高 基于维度发现的方法，以识别和在功能上验证控制高优先级分子 T细胞稳态。我们认为，该提案的成功完成将确定重要的体内稳态 对健康和其他疾病中T细胞稳态至关重要的信号传导机制。