The failure to generate enduring humoral immunity after vaccination is a hallmark of advancing age. This can be attributed to a reduction in the germinal center (GC) response, which generates long-lived antibody-secreting cells that protect against (re)infection. Despite intensive investigation, the primary cellular defect underlying impaired GCs in aging has not been identified. Here, we used heterochronic parabiosis to demonstrate that GC formation was dictated by the age of the lymph node (LN) microenvironment rather than the age of the immune cells. Lymphoid stromal cells are a key determinant of the LN microenvironment and are also an essential component underpinning GC structure and function. Using mouse models, we demonstrated that mucosal adressin cell adhesion molecule–1 (MAdCAM-1)–expressing lymphoid stromal cells were among the first cells to respond to NP-KLH + Alum immunization, proliferating and up-regulating cell surface proteins such as podoplanin and cell adhesion molecules. This response was essentially abrogated in aged mice. By targeting TLR4 using adjuvants, we improved the MAdCAM-1 + stromal cell response to immunization. This correlated with improved GC responses in both younger adult and aged mice, suggesting a link between stromal cell responses to immunization and GC initiation. Using bone marrow chimeras, we also found that MAdCAM-1 + stromal cells could respond directly to TLR4 ligands. Thus, the age-associated defect in GC and stromal cell responses to immunization can be targeted to improve vaccines in older people.

中文翻译：

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疫苗接种期间靶向 TLR4 可增强 MAdCAM-1 + 淋巴基质细胞活化并促进老化生发中心反应


接种疫苗后未能产生持久的体液免疫是衰老的标志。这可归因于生发中心（GC）反应的减少，该反应会产生长寿命的抗体分泌细胞，以防止（再次）感染。尽管进行了大量研究，但衰老过程中 GC 受损的主要细胞缺陷尚未确定。在这里，我们使用异时联体共生来证明 GC 的形成是由淋巴结 (LN) 微环境的年龄决定的，而不是免疫细胞的年龄。淋巴基质细胞是 LN 微环境的关键决定因素，也是支撑 GC 结构和功能的重要组成部分。使用小鼠模型，我们证明表达粘膜 adressin 细胞粘附分子 - 1 (MAdCAM-1) 的淋巴基质细胞是最早对 NP-KLH + Alum 免疫做出反应的细胞之一，能够增殖和上调细胞表面蛋白（如足足蛋白）和细胞粘附分子。这种反应在老年小鼠中基本上消失了。通过使用佐剂靶向 TLR4，我们改善了 MAdCAM-1 + 基质细胞对免疫的反应。这与年轻成年小鼠和老年小鼠的 GC 反应改善相关，表明基质细胞对免疫的反应与 GC 启动之间存在联系。使用骨髓嵌合体，我们还发现 MAdCAM-1 + 基质细胞可以直接响应 TLR4 配体。因此，可以针对GC和基质细胞对免疫反应的年龄相关缺陷来改进老年人的疫苗。