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

描述（由申请人提供）：IL-15是一种对记忆性CD 8 T细胞的产生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，这一机制尚未被清楚地理解。反式呈递是通过特定细胞类型递送细胞因子的机制，所述特定细胞类型通过高亲和力IL-15 Ra在细胞表面上表达IL- 15并将其呈递给相对细胞，从而诱导IL-15应答。到目前为止，很少有人知道介导这种功能的细胞类型或控制这种特定的细胞-细胞相互作用的参数。该提案的总体目标是更好地理解调节记忆性CD 8 T细胞的稳态增殖的机制。中心假设是树突状细胞（DC）通过IL-15反式呈递调节记忆性CD 8 T细胞的分化和稳态。这一假设是基于先前的数据得出的，这些数据表明，介导IL-15的反式呈递的IL-15 Ra的表达是造血细胞所需要的，而不是记忆CD 8 T细胞本身所需要的。目的1：检测DC介导的IL-15反式呈递在维持记忆性CD 8 T细胞中的作用。具体来说，将测试DC的IL-15 Ra表达是否足以维持记忆CD 8 T细胞稳态。此外，将评估DC数量的改变是否影响CD 8 T细胞稳态增殖以及DC与记忆性CD 8 T细胞相互作用的存在。目的2：确定特定DC亚群差异介导记忆性CD 8 T细胞稳态的程度。由于DC是异质的，因此将确定记忆性CD 8 T细胞稳态是否由特定DC亚群介导。目标3：确定记忆性CD 8 T细胞亚群稳态的差异是否是由于DC对IL-15反式呈递的不同需求所致。已经鉴定了记忆性CD 8 T细胞的两个主要亚群，其对体内稳态信号有差异性应答。将确定这是否是由于对DC介导的IL-15反式呈递的不同应答所致。这项研究的基本原理是，未来的研究可以确定必要的细胞特征和IL-15反式呈递的潜在调控因子。在理解CD 8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和使用CD 8 T细胞的过继疗法增强免疫疗法至关重要。

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.