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，导致感染和恶性肿瘤风险增加。随着年龄的增长，CD8+T细胞免疫最有趣的变化可能是记忆性CD8+T细胞的扩张，尽管这种现象的机制和后果很大程度上还不清楚(S)。最近，我的实验室研究了与年龄相关的记忆CD8+T细胞的扩张是否继发于IL-7受体阿尔法链(IL-7ra)的表达增加，而IL-7ra是CD8+T细胞生存的关键。在这项研究中，在CD45RA+效应记忆(EMCD45RA+，CD45RA+CCR7-)CD8+T细胞亚群中发现了高表达和低表达IL-7ra的细胞。与预期相反，与年轻人(年龄40岁)相比，老年人(65岁)有IL-7ra低EMCD45RA+CD8+T细胞(占总CD8+T细胞的25%)。这一发现引发了几个问题。这种细胞扩张是如何发生的？这种细胞扩增的免疫学后果(S)是什么？IL-7Ra低EMCD45RA+CD8+T细胞的增殖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CD8+T细胞随着年龄的增长而扩大有关。然而，这些细胞分别在IL-7和TCR的触发下存活和增殖很差，这表明仅靠IL-7或慢性TCR的触发都不足以解释这种现象。值得注意的是，IL-7Ra低CD8+T细胞在IL-15以及IL-15和TCR的共同触发下能够很好地增殖和扩增，这表明IL-15在扩增IL-7Ra低EMCD45RA+CD8+T细胞中起作用。因此，我推测IL-15对于随着年龄增长而扩增IL-7ra低EMCD45RA+CD8+T细胞至关重要，它通过诱导抗原非依赖性(单独使用IL-15)和依赖(TCR引发CMV，可能与IL-15共同作用)细胞的增殖来扩大IL-7ra低EMCD45RA+CD8+T细胞的功能。这一假说将针对以下具体目标：1)研究IL-7ra低EMCD45RA+CD8+T细胞随年龄增长是否与CMV感染直接相关；2)确定IL-7ra低EMCD45RA+CD8+T细胞随着年龄的增长是否因IL-15介导的CD8+T细胞增殖的改变而扩张；以及3)研究老年人中IL-7ra低EMCD45RA+CD8+T细胞是否发生了功能变化。这项研究的结果将加深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.