Regulatory T cells in the influenza response of the aged

描述(申请人提供)：老年人免疫系统最显著的变化之一是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，但也是老年人严重关切的问题，因为流感及其继发性并发症是美国65岁以上人口死亡的第四大原因。虽然与年龄相关的T细胞反应的改变归因于胸腺生成减少和维持外周淋巴细胞数量的动态平衡压力增加，但免疫力的急剧下降也可能反映了调节性T细胞(Treg)的存在。Treg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和传统的T细胞一样经历扩张，随着反应的进行，Tregs的抑制作用增强，从而维持反应的平衡。可以想象，随着年龄的增长，反复或长期接触病原体的机会增加，这种微妙的平衡可能会被Tregs的积累打破，这可能会抑制对这些病原体的反应。为此，在老年人类和老年小鼠中观察到Tregs的数量显著增加。这种随着年龄的增长而增加的频率有些自相矛盾。已有研究表明，Tregs由胸腺发育而来，而IL-2虽然不是胸腺Treg发育所必需的，但对于维持Tregs的外周状态和抑制Tregs的活动是至关重要的。然而，衰老与胸腺细胞的输出和T细胞产生IL-2的显著减少有关。那么Tregs的频率是如何随着年龄的增长而增加的呢？最近，有研究表明，在不理想的刺激条件下，可以从NAOVE CD4细胞的外周诱导出Tregs。此外，在正常的NAOVE小鼠中，已经显示出一部分Tregs在没有外源性抗原刺激的情况下缓慢增殖，推测是通过识别周围的自身抗原来实现的。因此，可以想象，随着年龄的增长，Tregs的积累可能是Tregs在外周产生和/或在生命早期产生Tregs的稳态扩张的结果。我们建议阐明Tregs在老年人中的存在增加的机制，并确定Tregs对流感病毒感染的免疫反应随着年龄的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(S)，还可能阐明减少它们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效力。

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.