The progressive impairment of immunity to pathogens and vaccines with aging is a significant public health problem as the world population shifts to an increased percentage of older adults (> 65). We have previously demonstrated that cells obtained from older volunteers have delayed and defective induction of type I interferons and T cell and B cell helper cytokines in response to TLR ligands when compared to those from adult subjects. However, the underlying intracellular mechanisms are not well described. Herein, we studied two critical pathways important in the production of type I interferon (IFN), the interferon response factor 7 (pIRF7), and TANK-binding kinase (pTBK-1). We show a decrease in pIRF7 and pTBK-1 in cross-priming dendritic cells (cDC1s), CD4⁺ T cell priming DCs (cDC2s), and CD14^dimCD16⁺ vascular patrolling monocytes from older adults (n = 11) following stimulation with pathway-specific agonists in comparison with young individuals (n = 11). The decrease in these key antiviral pathway proteins correlates with decreased phagocytosis, suggesting impaired function in Overall, our findings describe molecular mechanisms which explain the innate functional impairment in older adults and thus could inform us of novel approaches to restore these defects.

Graphical abstract

中文翻译：

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衰老改变抗病毒信号通路，导致先天免疫功能受损以响应模式识别受体激动剂

随着世界人口转向越来越多的老年人（> 65 岁），随着年龄的增长，对病原体和疫苗的免疫力逐渐受损是一个重大的公共卫生问题。我们之前已经证明，与来自成人受试者的细胞相比，从老年志愿者那里获得的细胞对 TLR 配体的反应延迟和缺陷诱导 I 型干扰素和 T 细胞和 B 细胞辅助细胞因子。然而，潜在的细胞内机制没有得到很好的描述。在此，我们研究了在 I 型干扰素 (IFN)、干扰素反应因子 7 (pIRF7) 和 TANK 结合激酶 (pTBK-1) 的产生中重要的两个关键途径。^{我们显示交叉启动树突细胞 (cDC1s)、CD4 +} T 细胞启动 DC (cDC2s) 和 CD14中的 pIRF7 和 pTBK-1 减少与年轻人 ( n  = 11) 相比，在用通路特异性激动剂刺激后，来自老年人 ( n = 11) 的^暗淡CD16 ⁺血管巡逻单核细胞 。这些关键抗病毒途径蛋白的减少与吞噬作用减少相关，表明功能受损 总的来说，我们的研究结果描述了解释老年人先天功能障碍的分子机制，因此可以告诉我们恢复这些缺陷的新方法。

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