Age-Dependent Decrease in the Induction of Regulatory T Cells Is Associated With Decreased Expression of RALDH2 in Mesenteric Lymph Node Dendritic Cells
Age-Dependent Decrease in the Induction of Regulatory T Cells Is Associated With Decreased Expression of RALDH2 in Mesenteric Lymph Node Dendritic Cells
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DOI：
10.3389/fimmu.2020.01555
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发表时间：
2020-08
影响因子：
7.3
通讯作者：
Tomohiro Takano;R. Kotaki;Jihyun Park;Tadashi Yoshida;Y. Wakatsuki;M. Tanokura;T. Miyakawa;Kyoko Takahashi;H. Nakajima-Adachi;S. Hachimura
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文献类型：
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作者：
Tomohiro Takano;R. Kotaki;Jihyun Park;Tadashi Yoshida;Y. Wakatsuki;M. Tanokura;T. Miyakawa;Kyoko Takahashi;H. Nakajima-Adachi;S. Hachimura
据报道，随着年龄的增长，免疫功能会下降。众所周知，调节性 T 细胞 (Treg) 的诱导会随着年龄的增长而减少，阐明其潜在机制对于预防因年龄相关的慢性炎症而导致的与年龄相关的疾病非常重要。在肠道中，树突状细胞 (DC) 在诱导针对口腔抗原的 Tregs 方面发挥着重要作用，它们通过在视黄醛脱氢酶 2 (RALDH2) 的催化下产生视黄酸 (RA)（一种维生素 A 代谢物）来有效诱导 Tregs。我们之前报道过，在肠系膜淋巴结（MLN）（诱导对口腔抗原的免疫反应的次级淋巴组织）中，四个 DC 亚群表达不同水平的 CD11b、CD103 和 PD-L1，并且我们报道过 CD11b–CD103+PD-L1high 亚群表达最高水平的 RALDH2 基因并在体外诱导 Tregs。我们通过给予食物抗原，使用 Treg 诱导模型检查了年轻和老年小鼠的 Treg 诱导，发现老年小鼠中抗原特异性 Treg 诱导减少。我们进一步研究了 MLN DC，在老年小鼠的 MLN DC 中观察到 RALDH2 基因表达显着下降。作为因素，我们发现与年轻小鼠相比，老年小鼠中 CD11b–CD103+PD-L1high 亚群的比例降低，并且 CD11b–CD103+PD-L1high 和 CD11b+CD103+PD-L1high 亚群中的 RALDH 酶活性降低。此外，对 RALDH2 基因启动子区域甲基化的分析表明，老年小鼠 MLN DC 中的 CpG 基序甲基化程度更高，表明 RALDH2 表达受到表观遗传变化的抑制。最后，我们发现 RA 治疗倾向于增加 Treg 诱导。这些结果表明，RA 产生的调节可能与年龄相关的抗原特异性 Treg 诱导减少有关。
A decline in immune function with aging has been reported. Regulatory T cell (Treg) induction is known to decrease with age, and elucidating the underlying mechanism is important for preventing age-related diseases due to age-related chronic inflammation. In the intestine, dendritic cells (DCs) play an important role in inducing Tregs specific to oral antigens, and they efficiently induce Tregs via production of retinoic acid (RA), a vitamin A metabolite, catalyzed by the enzyme retinaldehyde dehydrogenase 2 (RALDH2). We have previously reported that in the mesenteric lymph node (MLN), a secondary lymphoid tissue in which immune responses to oral antigens are induced, four DC subsets express different levels of CD11b, CD103, and PD-L1, and we have reported that the CD11b–CD103+PD-L1high subset expresses the highest levels of the RALDH2 gene and induces Tregs in vitro. We examined Treg induction in young and aged mice using a Treg induction model by administering a food antigen, and we found that antigen-specific Treg induction was decreased in aged mice. We further investigated the MLN DCs, and a significant decrease in RALDH2 gene expression was observed in MLN DCs from aged mice. As factors, we found that the proportion of the CD11b–CD103+PD-L1high subset was decreased in aged mice compared with that in young mice and that RALDH enzyme activity was decreased in the CD11b–CD103+PD-L1high and CD11b+CD103+PD-L1high subsets. Furthermore, analysis of the methylation of the RALDH2 gene promoter region revealed that CpG motifs were more methylated in the MLN DCs of aged mice, suggesting that RALDH2 expression was suppressed by epigenetic changes. Finally, we found that RA treatment tended to increase Treg induction. These results suggest that the regulation of RA production may be involved in the age-related decrease in antigen-specific Treg induction.