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

描述（由申请方提供）：T细胞免疫发生了与肿瘤相关的变化，导致感染和恶性肿瘤风险增加。也许，随着年龄的增长，CD 8 + T细胞免疫中最有趣的变化是记忆性CD 8 + 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，我的实验室研究了与年龄相关的记忆性CD 8 + T细胞的扩增是否继发于IL-7受体α链（IL-7 Ra）表达的增加，这对CD 8 + T细胞的存活至关重要。在这项研究中，在称为CD 45 RA+效应记忆（EMCD 45 RA+，CD 45 RA + CCR 7-）CD 8 + T细胞的记忆细胞亚群中发现了高表达和低表达IL-7 Ra的细胞。与预期相反，老年人（年龄：65岁）与年轻人（年龄：40岁）相比，IL-7 Ra低EMCD 45 RA + CD 8 + T细胞（占总CD 8 + T细胞的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后果是什么？IL-7 Ra低EMCD 45 RA + CD 8 + T细胞的扩增可能继发于感染（如巨细胞病毒（CMV））引起的慢性抗原刺激，这与记忆性CD 8 + T细胞随年龄增长的扩增有关。然而，这些细胞分别响应于IL-7和TCR触发而存活和增殖较差，表明单独的IL-7或慢性TCR触发都不足以解释这种现象。令人感兴趣的是，IL-7 Ra低CD 8 + T细胞响应于IL-15以及IL-15和TCR触发的组合而良好地增殖和扩增，这表明IL-15在扩增IL-7 Ra低EMCD 45 RA + CD 8 + T细胞中的作用。因此，我假设IL-15通过诱导抗原非依赖性（单独IL-15）和抗原依赖性（TCR触发，可能是CMV，与IL-15）细胞增殖，对随着衰老扩增IL-7 Ra低EMCD 45 RA + CD 8 + T细胞至关重要，并且这种扩增的细胞具有改变的功能。本研究的主要目的是：1）研究IL-7 Ra低水平的EMCD 45 RA + CD 8 + T细胞的增殖是否与CMV感染直接相关; 2）确定IL-7 Ra低水平的EMCD 45 RA + CD 8 + T细胞的增殖是否与IL-15介导的CD 8 + T细胞增殖的改变有关;和3）研究老年人中扩增的IL-7 Ra低EMCD 45 RA + CD 8 + T细胞是否具有改变的功能。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.