Department of Microbiology and Immunology, Faculty of Pharmacy, University of Belgrade, 450 Vojvode Stepe, 11221 Belgrade, Serbia.
Immunology Research Centre "Branislav Janković", Institute of Virology, Vaccines and Sera "Torlak", 458 Vojvode Stepe, 11221 Belgrade, Serbia.
Exp Gerontol. 2018 Jan;101:37-53. doi: 10.1016/j.exger.2017.11.002. Epub 2017 Nov 8.
The study investigated strain specificities in age-related differences in CD8+ T cell- and microglial cell-mediated mechanisms implicated in induction/perpetuation and/or control of neuroinflammation in experimental autoimmune encephalomyelitis (EAE) in Albino Oxford (AO) and Dark Agouti (DA) rats exhibiting age-related changes in the susceptibility to EAE in the opposite direction (increase in relatively resistant AO rats vs decrease in DA rats). In the inductive phase of EAE, the greater number of fully differentiated effector CD8+ T lymphocytes was found in draining lymph nodes (dLNs) from aged rats of both strains than in strain-matched young rats, but this was particularly prominent in AO rats, which exhibited milder EAE of prolonged duration compared with their DA counterparts. Consistently, dLN IFN-γ+ and IL-17+ CD8+ T cell counts were greater in aged AO than in DA rats. Additionally, the magnitudes of myelin basic protein (MBP)-induced rise in the frequency of IFN-γ+ and IL-17+ CD8+ T cells (providing important help to neuroantigen-specific CD4+ T cells in EAE models characterized by clinically mild disease) were greater in dLN cell cultures from aged AO rats. Consistently, the magnitudes of MBP-induced rise in the frequency of both IFN-γ+ and IL-17+ CD8+ T cells were greater in spinal cord mononuclear cell cultures from aged AO rats compared with their DA counterparts. Besides, with aging CD4+CD25+Foxp3+/CD8+CD25+Foxp3+ regulatory T cell ratio changed in spinal cord in the opposite direction. Consequently, in aged AO rats it was shifted towards CD8+CD25+Foxp3+ regulatory T cells (exhibiting lower suppressive capacity) when compared with DA rats. Moreover, the frequency of CX3CR1+ cells among microglia changed with aging and the disease development. In aged rats, in the effector phase of EAE it was lower in AO than in DA rats. This was accompanied by higher frequency of cells expressing IL-1β (whose down-regulation is central for CX3CR1-mediated neuroprotection), but lower that of phagocyting cells among microglia from aged AO compared their DA counterparts. The study indicates the control points linked with strain differences in age-related changes in EAE pathogenesis.
该研究调查了在实验性自身免疫性脑脊髓炎（EAE）中，与神经炎症的诱导/持续和/或控制有关的 CD8+T 细胞和小胶质细胞介导的机制在年龄相关差异中的菌株特异性，在这两种菌株的白化牛津（AO）和暗阿瓜提（DA）大鼠中，EAE 的易感性随着年龄的增长而发生相反的变化（相对抵抗性增加的 AO 大鼠与 DA 大鼠减少）。在 EAE 的诱导阶段，与同龄的年轻大鼠相比，来自两种菌株的老年大鼠引流淋巴结（dLN）中完全分化的效应 CD8+T 淋巴细胞的数量更多，但在 AO 大鼠中尤为明显，与 DA 大鼠相比，AO 大鼠的 EAE 较轻且持续时间较长。一致地，与 DA 大鼠相比，老年 AO 大鼠 dLN IFN-γ+和 IL-17+CD8+T 细胞计数更大。此外，在由髓鞘碱性蛋白（MBP）诱导的 IFN-γ+和 IL-17+CD8+T 细胞频率升高的幅度（在 EAE 模型中，对神经抗原特异性 CD4+T 细胞提供重要帮助，其疾病表现为临床轻度）在来自老年 AO 大鼠的 dLN 细胞培养物中更大。一致地，与 DA 大鼠相比，来自老年 AO 大鼠的脊髓单核细胞培养物中由 MBP 诱导的 IFN-γ+和 IL-17+CD8+T 细胞频率升高的幅度更大。此外，随着年龄的增长，CD4+CD25+Foxp3+/CD8+CD25+Foxp3+调节性 T 细胞比率在脊髓中发生相反的变化。因此，与 DA 大鼠相比，在老年 AO 大鼠中，它向 CD8+CD25+Foxp3+调节性 T 细胞（具有较低的抑制能力）转移。此外，小胶质细胞中 CX3CR1+细胞的频率随着年龄的增长和疾病的发展而变化。在老年大鼠中，在 EAE 的效应阶段，AO 大鼠的频率低于 DA 大鼠。这伴随着更高频率的表达 IL-1β 的细胞（其下调是 CX3CR1 介导的神经保护的核心），但与 DA 大鼠相比，来自老年 AO 的吞噬细胞频率较低。该研究表明了与 EAE 发病机制中年龄相关变化的菌株差异相关的控制点。
