Innate Lymphoid Cell Aging

项目摘要 先天性淋巴样细胞（ILC）是最近发现的组织驻留的自我更新免疫细胞， 在屏障防御、组织再生和免疫调节中起关键作用。我们的初步数据显示， 随着年龄的增长，ILC的数量逐渐减少。这个项目的目标是了解细胞和分子 导致ILC随年龄增长而丧失的机制，并检查ILC数量减少是否有助于 增加老年人对感染和疾病的易感性。该项目的重点是第2组先天 淋巴样细胞（ILC 2），肺中主要的ILC亚群。我们假设TCF-1的减少 表达损害ILC 2的自我更新，并导致ILC 2的数量随着年龄的增长而减少， ILC 2应答有助于增加老年人对流感感染的易感性。我们将使用新的TCF- 1 YFP和TCF-1条件性基因敲除小鼠，以探索控制细胞凋亡的细胞和分子机制。 肺驻留ILC 2的寿命和自我更新。我们将确定这些机制的失调是否 导致ILC 2随年龄增长而丧失。我们将进一步使用过继转移的方法来研究是否以及如何 降低的ILC 2应答有助于增加老年小鼠对流感的易感性。最后我们将 制定策略以恢复老年人的ILC 2数量，并将测试这些策略的有效性， 增强老年小鼠对流感的抵抗力。我们预计，这项工作将提供重要的见解， 淋巴细胞老化，并将为改善老年人免疫防御的策略提供信息。

Project Summary Innate lymphoid cells (ILC) are recently discovered tissue-resident self-renewing immune cells with critical roles in barrier defense, tissue regeneration and immune regulation. Our preliminary data indicate that ILC gradually diminish in number with age. The goal of this project is to understand the cellular and molecular mechanisms that result in loss of ILC with age, and to examine whether diminished ILC numbers contribute to increased susceptibility to infections and diseases in the aged. This project focuses on group-2 innate lymphoid cells (ILC2), the predominant ILC subset in the lung. We hypothesize that decreased TCF-1 expression impairs ILC2 self-renewal and results in diminished numbers of ILC2 with age, and that diminished ILC2 responses contribute to increased susceptibility to influenza infection in the aged. We will use novel TCF- 1YFP and TCF-1 conditional knockout mice to explore the cellular and molecular mechanisms that control the longevity and self-renewal of lung-resident ILC2. We will determine whether dysregulation of such mechanisms results in loss of ILC2 with age. We will further use adoptive transfer approaches to examine whether and how diminished ILC2 responses contribute to increased susceptibility to influenza in aged mice. Finally, we will develop strategies to restore ILC2 numbers in the aged, and will test the efficacy of these strategies to enhance resistance to influenza in old mice. We anticipate that this work will provide significant insights into lymphocyte aging, and will inform strategies to improve immune defense in the elderly.