Regulatory T cells in the influenza response of the aged

调节性 T 细胞在老年人流感反应中的作用

• 批准号: 7904558
• 负责人: Phyllis-Jean Linton
• 金额: $ 15.32万
• 依托单位: SAN DIEGO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-15 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904558
• 关键词: Influenza; T-Lymphocyte; aged; response

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.

描述（由申请人提供）：老年人免疫系统中最值得注意的变化是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，但对于老年人来说是一个严重的问题，因为流感及其继发性并发症是美国65岁以上人群死亡的第四大原因。虽然T细胞应答的年龄相关变化归因于胸腺生成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（TcR）的存在。它不仅能预防自身免疫，还能控制广泛的免疫反应，包括抑制移植排斥反应、预防抗肿瘤反应的诱导和调节对感染性病原体的免疫反应。在抗原刺激后，TcR与常规T细胞一样经历扩增，并且随着应答的进展，TcR的抑制增加，从而维持应答平衡。可以想象的是，随着年龄的增长，其中复发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Tcl 3的积累所破坏，Tcl 3的积累可能会抑制对这些病原体的反应。为此，已经观察到老年人和老年小鼠中TbR的数量显著增加。随着年龄的增长，这种频率的增加有点自相矛盾。已经表明，T细胞从胸腺发育，并且IL-2虽然对于胸腺中的Treg发育不是必需的，但是对于外周中T细胞的维持和T细胞的抑制活性是关键的。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，甲状腺激素是如何随着年龄的增长而增加的呢？最近，已经证明，在次优刺激条件下，可以在外周中从幼稚CD 4细胞诱导TcB。此外，在正常的naove小鼠中，一部分TcB已经显示出在没有外源性抗原刺激的情况下缓慢增殖，推测是通过识别外周中的自身抗原。因此，可以想象的是，随着年龄的增长，T细胞的积累可能是在外周产生T细胞和/或在生命早期产生的T细胞的稳态扩张的结果。我们建议阐明老年人中THBE存在增加的机制，并确定THBE对流感病毒感染免疫应答随年龄增长而总体下降的相对贡献。公共卫生关系：这些研究的结果不仅将阐明THBE数量增加的可能机制，还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有效性。