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

描述(申请人提供)：IL-15是一种细胞因子，对记忆性CD8 T细胞的产生和维持都至关重要。然而，IL-15的功能是通过一种称为反式递呈的新机制来调节的，这一机制目前还不清楚。反式递呈是一种由特定类型的细胞递送细胞因子的机制，它通过高亲和力的IL-15ra在细胞表面表达IL-15，并将其呈递给对方细胞，从而诱导IL-15反应。到目前为止，人们对介导这一功能的细胞类型或控制这一特定细胞-细胞相互作用的参数知之甚少。这项建议的总体目标是更好地了解调节记忆CD8 T细胞内稳态增殖的机制。中心假说是树突状细胞(DC)通过IL-15反式递呈调节记忆性CD8 T细胞的分化和动态平衡。这一假说是基于先前的数据，即介导IL-15反式表达的IL-15ra是造血细胞所必需的，而不是记忆CD8 T细胞本身所需要的。该方案的具体目的是：目的1：研究DC介导的IL-15反式递呈在维持记忆CD8 T细胞中的作用。具体来说，将测试DC表达IL-15ra是否足以维持记忆性CD8 T细胞的动态平衡。此外，还将评估DC数量的变化是否影响CD8 T细胞的稳态增殖，以及DC与记忆CD8 T细胞之间是否存在相互作用。目的2：确定特定DC亚群在多大程度上不同地调节记忆性CD8 T细胞的稳态。由于DC是异质性的，因此将确定记忆CD8 T细胞的稳态是否由特定的DC亚群介导。目的3：确定记忆性CD8 T细胞亚群动态平衡的差异是否源于DC对IL-15反式递呈的不同要求。在体内，已经确定了两个主要的记忆CD8T细胞亚群，它们对内环境平衡信号有不同的反应。将确定这是否由于DC介导的IL-15反式递呈的不同反应所致。这项研究的基本原理是，这样未来的研究就可以确定必要的细胞特征和IL-15反式递呈的潜在调节因素。了解CD8记忆T细胞动态平衡领域的科学进展对于设计疫苗、保持对感染的免疫力以及使用CD8 T细胞过继疗法加强免疫治疗至关重要。

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.