Da Mesquita Sandro, Herz Jasmin, Wall Morgan, Dykstra Taitea, de Lima Kalil Alves, Norris Geoffrey T, Dabhi Nisha, Kennedy Tatiana, Baker Wendy, Kipnis Jonathan
Department of Neuroscience, Center for Brain Immunology and Glia (BIG), University of Virginia, Charlottesville, VA, USA.
Center for Brain Immunology and Glia (BIG), Washington University in St. Louis, St. Louis, MO, USA.
Sci Adv. 2021 May 21;7(21). doi: 10.1126/sciadv.abe4601. Print 2021 May.
Aging leads to a progressive deterioration of meningeal lymphatics and peripheral immunity, which may accelerate cognitive decline. We hypothesized that an age-related reduction in C-C chemokine receptor type 7 (CCR7)-dependent egress of immune cells through the lymphatic vasculature mediates some aspects of brain aging and potentially exacerbates cognitive decline and Alzheimer's disease-like brain β-amyloid (Aβ) pathology. We report a reduction in CCR7 expression by meningeal T cells in old mice that is linked to increased effector and regulatory T cells. Hematopoietic CCR7 deficiency mimicked the aging-associated changes in meningeal T cells and led to reduced glymphatic influx and cognitive impairment. Deletion of CCR7 in 5xFAD transgenic mice resulted in deleterious neurovascular and microglial activation, along with increased Aβ deposition in the brain. Treating old mice with anti-CD25 antibodies alleviated the exacerbated meningeal regulatory T cell response and improved cognitive function, highlighting the therapeutic potential of modulating meningeal immunity to fine-tune brain function in aging and in neurodegenerative diseases.
衰老会导致脑膜淋巴管和外周免疫功能逐渐衰退，这可能会加速认知能力下降。我们推测，与年龄相关的通过淋巴管系统的C-C趋化因子受体7（CCR7）依赖性免疫细胞流出减少介导了脑衰老的某些方面，并可能加剧认知能力下降和阿尔茨海默病样脑β-淀粉样蛋白（Aβ）病理变化。我们报告了老年小鼠脑膜T细胞中CCR7表达的减少，这与效应T细胞和调节性T细胞的增加有关。造血CCR7缺陷模拟了脑膜T细胞中与衰老相关的变化，并导致糖淋巴流入减少和认知障碍。在5xFAD转基因小鼠中删除CCR7会导致有害的神经血管和小胶质细胞激活，同时大脑中Aβ沉积增加。用抗CD25抗体治疗老年小鼠可减轻脑膜调节性T细胞反应的加剧，并改善认知功能，突出了调节脑膜免疫以微调衰老和神经退行性疾病中脑功能的治疗潜力。
