Department of Microbiology, Immunology, and Genetics, University of North Texas Health Science Center, Fort Worth, Texas, USA.
Alcon Research, LLC, Fort Worth, Texas, 76134, USA.
Aging Cell. 2022 Jun;21(6):e13630. doi: 10.1111/acel.13630. Epub 2022 May 26.
Although typically associated with onset in young adults, multiple sclerosis (MS) also attacks the elderly, which is termed late-onset MS. The disease can be recapitulated and studied in a mouse model, experimental autoimmune encephalomyelitis (EAE). The onset of induced EAE is delayed in aged mice, but disease severity is increased relative to young EAE mice. Given that CD4 FoxP3 regulatory T (Treg) cells play an ameliorative role in MS/EAE severity, and the aged immune system accumulates peripheral Treg (pTreg) cells, failure of these cells to prevent or ameliorate EAE disease is enigmatic. When analyzing the distribution of Treg cells in EAE mice, the aged mice exhibited a higher proportion of polyclonal (pan-) pTreg cells and a lower proportion of antigen-specific pTreg cells in the periphery but lower proportions of both pan- and antigen-specific Treg cells in the central nervous system (CNS). Furthermore, in the aged inflamed CNS, CNS-Treg cells exhibited a higher plasticity, and T effector (CNS-Teff) cells exhibited greater clonal expansion, disrupting the Treg/Teff balance. Transiently inhibiting FoxP3 or depleting pTreg cells partially corrected Treg distribution and restored the Treg/Teff balance in the aged inflamed CNS, thereby ameliorating the disease in the aged EAE mice. These results provide evidence and mechanism that accumulated aged pTreg cells play a detrimental role in neuronal inflammation of aged MS.
尽管多发性硬化症（MS）通常与年轻人发病有关，但它也会攻击老年人，这种情况被称为迟发性 MS。这种疾病可以在小鼠模型中被重现和研究，即实验性自身免疫性脑脊髓炎（EAE）。诱导的 EAE 在老年小鼠中的发病时间延迟，但与年轻的 EAE 小鼠相比，疾病的严重程度增加。鉴于 CD4 FoxP3 调节性 T（Treg）细胞在 MS/EAE 严重程度中发挥改善作用，并且衰老的免疫系统会积累外周 Treg（pTreg）细胞，这些细胞未能预防或改善 EAE 疾病是一个谜。在分析 EAE 小鼠中 Treg 细胞的分布时，老年小鼠在外周血中表现出更高比例的多克隆（pan-）pTreg 细胞和更低比例的抗原特异性 pTreg 细胞，但在中枢神经系统（CNS）中这两种细胞的比例均较低。此外，在衰老的炎症性中枢神经系统中，CNS-Treg 细胞表现出更高的可塑性，CNS-T 效应（CNS-Teff）细胞表现出更大的克隆扩增，破坏了 Treg/Teff 平衡。短暂抑制 FoxP3 或耗竭 pTreg 细胞部分纠正了 Treg 的分布，并恢复了衰老的炎症性中枢神经系统中的 Treg/Teff 平衡，从而改善了老年 EAE 小鼠的疾病。这些结果提供了证据和机制，表明积累的衰老 pTreg 细胞在衰老 MS 的神经元炎症中发挥有害作用。
