Age-Associated Decrease in TLR Function in Primary Human Dendritic Cells Predicts Influenza Vaccine Response
Age-Associated Decrease in TLR Function in Primary Human Dendritic Cells Predicts Influenza Vaccine Response
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DOI：
10.4049/jimmunol.0901022
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发表时间：
2010-03-01
影响因子：
4.4
通讯作者：
Shaw, Albert C.
中科院分区：
文献类型：
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作者：
Panda, Alexander;Qian, Feng;Shaw, Albert C.
我们评估了104名年轻人（21 - 30岁）和老年人（≥65岁）的原代人树突状细胞（DCs）中的Toll样受体（TLR）功能。我们使用多色流式细胞术以及髓样树突状细胞（mDCs）和浆细胞样树突状细胞（pDCs）的细胞内细胞因子染色，发现与年轻人相比，老年人的mDCs在受到TLR1/2、TLR2/6、TLR3、TLR5和TLR8刺激时产生的肿瘤坏死因子 -α（TNF -α）、白细胞介素 - 6（IL - 6）和/或白细胞介素 - 12（p40），以及pDCs在受到TLR7和TLR9刺激时产生的TNF -α和干扰素 -α显著减少。在使用混合效应统计模型对年轻人和老年人组之间的异质性（例如性别、种族、体重指数、合并疾病数量）进行调整后，这些差异具有高度显著性。对纯化的mDCs和pDCs中TLR蛋白的表面和细胞内表达以及TLR基因表达的研究揭示了转录和转录后机制在这些与年龄相关的效应中的潜在作用。此外，在没有TLR配体刺激的情况下，老年人细胞内的细胞因子产生高于年轻人，这表明细胞因子产生的失调可能会限制TLR激活后的进一步活化。我们的结果为树突状细胞的免疫衰老提供了证据；值得注意的是，细胞因子产生的缺陷与流感疫苗接种后的抗体反应不良密切相关，这是衰老的先天免疫反应中TLR功能受损的一个功能性后果。《免疫学杂志》，2010年，184卷：2518 - 2527页。
We evaluated TLR function in primary human dendritic cells (DCs) from 104 young (age 21-30 y) and older (>= 65 y) individuals. We used multicolor flow cytometry and intracellular cytokine staining of myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) and found substantial decreases in older compared with young individuals in TNF-alpha, IL-6, and/or IL-12 (p40) production in mDCs and in TNF-alpha and IFN-alpha production in pDCs in response to TLR1/2, TLR2/6, TLR3, TLR5, and TLR8 engagement in mDCs and TLR7 and TLR9 in pDCs. These differences were highly significant after adjustment for heterogeneity between young and older groups (e.g., gender, race, body mass index, number of comorbid medical conditions) using mixed-effect statistical modeling. Studies of surface and intracellular expression of TLR proteins and of TLR gene expression in purified mDCs and pDCs revealed potential contributions for both transcriptional and posttranscriptional mechanisms in these age-associated effects. Moreover, intracellular cytokine production in the absence of TLR ligand stimulation was elevated in cells from older compared with young individuals, suggesting a dysregulation of cytokine production that may limit further activation by TLR engagement. Our results provide evidence for immunosenescence in DCs; notably, defects in cytokine production were strongly associated with poor Ab response to influenza immunization, a functional consequence of impaired TLR function in the aging innate immune response. The Journal of Immunology, 2010, 184: 2518-2527.