Aging and IL-7-mediated CD8+ T Cell survival

描述（由申请人提供）：T细胞免疫发生与年龄相关的变化，增加感染和恶性肿瘤的风险。也许，随着年龄的增长，CD8+ T细胞免疫中最有趣的变化是记忆性CD8+ T细胞扩增，尽管这种现象的机制和后果在很大程度上是未知的。最近，我的实验室研究了记忆性CD8+ T细胞的年龄相关扩增是否继发于对CD8+ T细胞存活至关重要的IL-7受体α链（IL-7Ra）的表达增加。在这项研究中，IL-7Ra高表达和低表达的细胞存在于被称为CD45RA+效应记忆（EMCD45RA+, CD45RA+ CCR7-） CD8+ T细胞的记忆细胞亚群中。与预期相反，老年人（65岁）与年轻人（40岁）相比，IL-7Ra低EMCD45RA+ CD8+ T细胞（占CD8+ T细胞总数的25%）扩增。这一发现提出了几个问题。这种细胞扩张是如何发生的？这种细胞扩增的免疫学结果是什么？IL-7Ra低EMCD45RA+ CD8+ T细胞的扩增可能继发于巨细胞病毒（CMV）等感染的慢性抗原刺激，这与记忆性CD8+ T细胞随着年龄的增长而扩增有关。然而，这些细胞分别在IL-7和TCR触发下存活和增殖较差，这表明单独触发IL-7和慢性TCR都不能充分解释这一现象。有趣的是，IL-7Ra低CD8+ T细胞在IL-15以及IL-15和TCR的联合触发下很好地增殖和扩增，这表明IL-15在IL-7Ra低EMCD45RA+ CD8+ T细胞扩增中的作用。因此，我假设IL-15通过诱导抗原非依赖性（单独IL-15）和依赖性（TCR触发，可能是CMV，与IL-15一起）细胞增殖，对IL-7Ra低EMCD45RA+ CD8+ T细胞的增殖至关重要，并且这种扩增的细胞已经改变了功能。这一假说的具体目的如下：1)研究IL-7Ra低EMCD45RA+ CD8+ T细胞随着年龄的增长是否与CMV感染有直接关系；2)确定IL-7Ra低EMCD45RA+ CD8+ T细胞的扩增是否源于il -15介导的CD8+ T细胞增殖的改变；3)探讨老年人IL-7Ra扩增低EMCD45RA+ CD8+ T细胞功能是否发生改变。这项研究的结果将促进我们对衰老对免疫系统影响的理解，从而更好地预防感染和肿瘤。

DESCRIPTION (provided by applicant): Age-associated changes occur in T cell immunity, contributing to increased risk of infection and malignancy. Probably, the most intriguing alteration in CD8+ T cell immunity with aging is memory CD8+ T cell expansion although the mechanism(s) and the consequences of this phenomenon are largely unknown. Recently, my lab investigated whether the age-associated expansion of memory CD8+ T cells was secondary to increased expression of IL-7 receptor alpha chain (IL-7Ra) which is critical for CD8+ T cell survival. In this study, cells expressing IL-7Ra high and low were found in a subset of memory cells called CD45RA+ effector memory (EMCD45RA+, CD45RA+ CCR7-) CD8+ T cells. In contrast to the expectation, the elderly (age ¿: 65) had expansion of IL-7Ra low EMCD45RA+ CD8+ T cells (25% of total CD8+ T cells) compared to the young (age ¿ 40). This finding raises several questions. How does such cell expansion occur? What is the immunologic consequence(s) of this cell expansion? The expansion of IL-7Ra low EMCD45RA+ CD8+ T cells could be secondary to chronic antigen stimulations by infections such as cytomegalovirus (CMV), which has been linked to the expansion of memory CD8+ T cells with aging. However, these cells poorly survive and proliferate in response to IL-7 and TCR triggering, respectively, indicating that neither IL-7 nor chronic TCR triggering alone is sufficient explanation for this phenomenon. Of interest, IL-7Ra low CD8+ T cells nicely proliferate and expand in response to IL-15 and a combination of IL-15 and TCR triggering, which suggests the role for IL-15 in expanding IL-7Ra low EMCD45RA+ CD8+ T cells. Thus, I hypothesize that IL-15 is critical for expanding IL-7Ra low EMCD45RA+ CD8+ T cells with aging via inducing antigen-independent (IL-15 alone) and -dependent (TCR triggering, possibly CMV, with IL-15) cell proliferation, and such expanded cells have altered functions. This hypothesis will be addressed with the following specific aims: 1) Investigate whether the expansion of IL-7Ra low EMCD45RA+ CD8+ T cells with aging is directly related to CMV infection; 2) Determine whether the expansion of IL-7Ra low EMCD45RA+ CD8+ T cells with aging steins from alterations in IL-15-mediated CD8+ T cell proliferation; and 3) Investigate whether expanded IL-7Ra low EMCD45RA+ CD8+ T cells in the elderly have altered function. The results of this study will advance our understanding about the effect of aging on the immune system, leading to better protection against infection and tumors.