Regulation of memory CD8 T Cell homeostasis by IL-15Ra+

IL-15Ra 对记忆 CD8 T 细胞稳态的调节

• 批准号: 7477776
• 负责人: KIMBERLY Sue SCHLUNS
• 金额: $ 35.72万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477776
• 关键词: Affect; Affinity; Antigens; Automobile Driving; Binding; Binding Proteins; Biological Models; CD8B1 gene; Cell Communication; Cell Count; Cell surface; Cells; Cellular biology; Complex; Data; Dendritic Cells; Environment; Future; Generations; Goals; Hematopoietic; Homeostasis; Immune response; Immunity; Immunotherapy; Infection; Interleukin-15; Investigation; Knowledge; Learning; Maintenance; Mediating; Memory; Modeling; Population; Population Heterogeneity; Process; Regulation; Research Personnel; Role; Signal Transduction; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Thinking; Vaccine Design; cell type; cytokine; in vivo; in vivo Model; interleukin-15 receptor; novel; programs; receptor binding; response

DESCRIPTION (provided by applicant): IL-15 is a cytokine crucial for both the generation and the maintenance of memory CD8 T cells. However, the functions of IL-15 are mediated via a novel mechanism called trans-presentation, which is not yet clearly understood. Trans-presentation is a mechanism of cytokine delivery by a specific cell type that expresses IL- 15 on the cell surface via a high affinity IL-15Ra and presents it to an opposing cell, thus inducing an IL-15 response. As yet, little is known about the cell types mediating this function or the parameters controlling this specific cell-cell interaction. The overall objective of this proposal is to better understand the mechanism that regulates the homeostatic proliferation of memory CD8 T cells. The central hypothesis is that dendritic cells (DCs) regulate the differentiation and homeostasis of memory CD8 T cells via IL-15 trans-presentation. This hypothesis is drawn on previous data demonstrating that expression of IL-15Ra, which mediates trans- presentation of IL-15, is required by hematopoietic cells but not by memory CD8 T cells themselves. The specific aims of this proposal are: Aim 1: Examine the contribution of DC-mediated IL-15 trans-presentation in the maintenance of memory CD8 T cells. Specifically, whether DCs expression of IL-15Ra is sufficient for memory CD8 T cell homeostasis will be tested. In addition, whether alterations in DC numbers affect CD8 T cell homeostatic proliferation and the existence of DCs interactions with memory CD8 T cells will be assessed. Aim 2: Determine the extent to which specific DC subsets differentially mediate memory CD8 T cell homeostasis. As DCs are heterogeneous, it will be determined if memory CD8 T cell homeostasis is mediated by a specific DC subset. Aim 3: Identify if differences in the homeostasis of memory CD8 T cell subsets are due to differential requirements for IL-15 trans-presentation by DCs. Two major subsets of memory CD8 T cells have been identified that differentially respond to homeostatic signals in vivo. It will be determined if this is due to differential responses to DC-mediated IL-15 trans-presentation. The rationale for this study is so future investigations can identify the necessary cellular features and potential regulators of IL-15 trans-presentation. The scientific progress in understanding the field of CD8 memory T cell homeostasis is crucial for designing vaccines, maintaining immunity to infections, and enhancing immunotherapy using adoptive therapies of CD8 T cells.

描述（由申请人提供）：IL-15 是一种对于记忆 CD8 T 细胞的生成和维持至关重要的细胞因子。然而，IL-15 的功能是通过一种称为反式呈递的新机制介导的，目前尚不清楚。反式呈递是通过高亲和力IL-15Ra在细胞表面表达IL-15并将其呈递给相反细胞的特定细胞类型递送细胞因子的机制，从而诱导IL-15应答。迄今为止，人们对介导这种功能的细胞类型或控制这种特定细胞间相互作用的参数知之甚少。该提案的总体目标是更好地了解调节记忆 CD8 T 细胞稳态增殖的机制。中心假设是树突状细胞 (DC) 通过 IL-15 反式呈递调节记忆 CD8 T 细胞的分化和稳态。这一假设是根据先前的数据得出的，该数据表明造血细胞需要介导 IL-15 转呈的 IL-15Ra 的表达，但记忆 CD8 T 细胞本身不需要。该提案的具体目标是： 目标 1：检查 DC 介导的 IL-15 反式呈递在维持记忆 CD8 T 细胞中的贡献。具体来说，将测试IL-15Ra的DC表达是否足以维持记忆CD8 T细胞稳态。此外，还将评估 DC 数量的变化是否影响 CD8 T 细胞稳态增殖以及 DC 与记忆 CD8 T 细胞相互作用的存在。目标 2：确定特定 DC 亚群差异介导记忆 CD8 T 细胞稳态的程度。由于 DC 是异质的，因此将确定记忆 CD8 T 细胞稳态是否由特定 DC 子集介导。目标 3：确定记忆 CD8 T 细胞亚群的稳态差异是否是由于 DC 对 IL-15 反式呈递的不同要求造成的。已确定记忆 CD8 T 细胞的两个主要亚群对体内稳态信号有不同的反应。将确定这是否是由于对 DC 介导的 IL-15 反式呈递的差异反应所致。这项研究的基本原理是，未来的研究可以确定 IL-15 反式呈递的必要细胞特征和潜在调节因子。了解 CD8 记忆 T 细胞稳态领域的科学进展对于设计疫苗、维持对感染的免疫力以及使用 CD8 T 细胞过继疗法增强免疫治疗至关重要。