Identifying Mechanisms Governing T Cell Diversity

项目概要 适应性免疫系统的特点是多样性和记忆性。多样化的 T 细胞库对于 确保有效防御几乎无限数量的潜在病毒、真菌和细菌病原体。时间 细胞多样性是在胸腺中产生的。由于 T 细胞受体组装不精确，超过 108 个 T 细胞克隆被 胸腺中产生，每种都表达独特的 T 细胞受体。在成年早期，胸腺 渐开线。因此，为了维持健康的免疫系统，必须维持 T 细胞的多样性。 免疫外围。 T 细胞多样性的维持需要微调，因为微小的扰动 随着时间的推移，T 细胞库会对 T 细胞多样性产生巨大影响。每个克隆必须支持 积极的稳态信号可以使人生存数十年。同时，每个克隆不得 过度增殖。由于免疫空间似乎是固定的，个体 T 细胞的过度扩张 克隆可能会排挤它的邻居。尽管 T 细胞稳态对于 对于人类健康和疾病，我们缺乏对如何维持 T 细胞多样性的机制洞察。有两个 进步的重要障碍。其一，人类研究通常集中于相对较小、不相关的领域 表型异质的老年人群。其次，复杂异质性的研究 细胞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 表型相似的人类异常群体，他们的 T 细胞库发生了深刻的改变，即 皮肤T细胞淋巴瘤（CTCL）患者。 CTCL 是一种无法治愈的皮肤非霍奇金淋巴瘤 归巢 CD4 T 细胞。晚期白血病 CTCL 患者总是出现细胞过度增殖 恶性 T 细胞克隆以及良性、未转化的 CD4 和 CD8 T 细胞的严重损失。这个 淋巴细胞减少症是疾病的一个特征，以阶段依赖的方式发展，并且在以下情况中是不可避免的： 患有 IV 期疾病的患者。据推测，正常 T 细胞的丧失通过抑制 抗肿瘤免疫力。新出现的数据表明，这两种相反的趋势是由于病理性的原因而发生的。 保持克隆存活的稳态信号的改变以及阻止克隆的稳态信号的改变 人口过度拥挤。我们推测 CTCL 肿瘤细胞的阳性细胞过度激活 稳态信号和对负稳态信号的抵抗。相反，消失的、良性的 CTCL患者的T细胞对正稳态信号相对抵抗，并对稳态信号高度敏感。 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来识别和功能验证控制的高优先级分子 T 细胞稳态。我们相信，成功完成该提案将确定重要的稳态 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。

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.