Regulatory T cells in the influenza response of the aged

描述（由申请人提供）：老年人免疫系统中最显著的变化是T细胞对病原体的反应急剧下降。流感是普通人群发病和死亡的主要原因，但对老年人来说是一个严重的问题，因为流感及其继发并发症是美国65岁以上人群死亡的第四大原因。虽然年龄相关的T细胞反应变化归因于胸腺增生减少和维持外周淋巴细胞数量的稳态压力增加，但免疫力的急剧下降也可能反映了调节性T细胞（Tregs）的存在。Tregs不仅可以预防自身免疫，还可以控制广泛的免疫反应，包括抑制移植排斥反应，防止诱导抗肿瘤反应，以及调节对感染性病原体的免疫反应。在抗原刺激下，Tregs和常规T细胞一样会扩增，随着应答的进行，Tregs的抑制作用增强，从而维持应答的平衡。可以想象，随着年龄的增长，反复或慢性暴露于病原体的机会增加，这种微妙的平衡可能会被treg的积累所打破，treg可能会抑制对这些病原体的反应。为此，观察到老年人和老年小鼠中treg的数量显著增加。treg随着年龄的增长而增加的频率有些矛盾。研究表明，Treg从胸腺发育而来，IL-2虽然不是胸腺Treg发育所必需的，但对于维持周围Treg和抑制Treg活性至关重要。然而，衰老与胸腺细胞输出和T细胞产生IL-2的显著减少有关。那么Tregs是如何随着年龄的增长而增加的呢？最近，研究表明，在次优刺激条件下，外周细胞可以从幼稚的CD4细胞中诱导Tregs。此外，在正常的幼年小鼠中，部分Tregs已被证明在没有外源抗原刺激的情况下缓慢增殖，可能是通过外周自身抗原的识别。因此，可以想象，随着年龄的增长，treg的积累可能是外围细胞中treg的产生和/或生命早期产生的treg的稳态扩张的结果。我们建议阐明Tregs在老年人中增加存在的机制，并确定Tregs对流感病毒感染免疫反应随年龄增长而整体下降的相对贡献。公共卫生相关性：这些研究的结果不仅将阐明treg数量增加的可能机制，而且可能阐明减少其对流感反应的负面影响的方法，并可能有助于提高当前和未来疫苗的功效。

DESCRIPTION (provided by applicant): Among the most noted changes in the immune system of the aged is the dramatic decline in T cell responses to pathogens. Influenza is a major cause of morbidity and mortality in the general population, but is a serious concern for the elderly, as influenza and its secondary complications represent the fourth leading cause of death in persons over the age of 65 in the United States. While age-related alterations in T cell responses are attributed to reduced thymopoiesis and increased homeostatic pressures to maintain lymphocyte numbers in the periphery, the dramatic decline in immunity may also reflect the presence of regulatory T cells (Tregs). Tregs not only prevent autoimmunity, but control a broad range of immune responses including the inhibition of transplant rejection, the prevention of the induction of anti-tumor responses, and the regulation of immune responses to infectious pathogens. Upon antigen stimulation Tregs, like conventional T cells, undergo expansion and as the response progresses, suppression by Tregs increases thereby maintaining the response in equilibrium. It is conceivable that with aging, wherein the chance for recurrent or chronic exposure to pathogens increases, this delicate balance may be upset by an accumulation of Tregs, which can potentially suppress responses to these pathogens. To this end, a significant increase in the number of Tregs in aged humans and aged mice has been observed. This increased frequency in Tregs with aging is somewhat paradoxical. It has been shown that Tregs develop from the thymus, and IL-2, although not essential for Treg development in the thymus, is critical for the maintenance of Tregs in the periphery and for the suppressive activity of Tregs. Yet, aging is associated with a marked reduction in both the export of thymocytes and the production of IL-2 by T cells. So how do Tregs increase in frequency with aging? Recently, it has been demonstrated that Tregs can be induced in the periphery from naove CD4 cells upon suboptimal stimulatory conditions. Furthermore, in normal naove mice, a fraction of Tregs has been shown to slowly proliferate without exogenous antigenic stimulation, presumably through the recognition of self-antigens in the periphery. Thus, it is conceivable that the accumulation of Tregs with aging may be the consequence of the generation of Tregs in the periphery and/or homeostatic expansion of Tregs that were generated earlier in life. We propose to elucidate the mechanism for the increased presence of Tregs in the aged and to determine the relative contribution by Tregs to the overall decline with aging in the immune response to influenza virus infection. PUBLIC HEALTH RELEVANCE: Findings from these studies will not only elucidate possible mechanism(s) for the increased number of Tregs but potentially elucidate methods to reduce their negative influence on influenza responses and possibly aid in improving the efficacy of current and future vaccines.