Djuretić Jasmina, Pilipović Ivan, Stojić-Vukanić Zorica, Leposavić Gordana
Department of Pathobiology, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Immunology Research Center "Branislav JankoviĆ", Institute of Virology, Vaccines and Sera "Torlak", Belgrade, Serbia.
Cent Eur J Immunol. 2019;44(4):337-356. doi: 10.5114/ceji.2019.92777. Epub 2020 Jan 20.
Natural killer (NK) cells, influencing dendritic cell (DC)-mediated CD4+ lymphocyte priming in draining lymph nodes (dLNs) and controlling spinal cord (SC) infiltration with encephalitogenic CD4+T lymphocytes, modulate EAE (multiple sclerosis model). This study examined their putative contribution to age-related differences in EAE development in Dark Agouti (DA) (exhibiting age-related decrease in EAE susceptibility) and Albino Oxford (AO) (becoming susceptible to EAE with aging) rats. Aging increased NK cell number in dLNs from rats of both strains. In AO rats, but not in DA ones, it also increased the numbers of IFN-γ-producing NK cells (important for DC activation) and activated/matured DCs, thereby increasing activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated CD25+Foxp3-CD4+ cell number. Aging in DA rats diminished activated/matured DC/conventional Foxp3-CD4+ cell ratio and activated Foxp3-CD4+ cell number. However, MBP-stimulated CD4+ cell proliferation did not differ in dLN cell cultures from young and aged AO rats (as more favorable activated/matured DC/Foxp3-CD4+ cell ratio was abrogated by lower intrinsic CD4+ cell proliferative capacity and a greater regulatory CD25+Foxp3+CD4+ lymphocyte frequency), but was lower in those from aged compared with young DA rats. At SC level, aging shifted Foxp3-CD4+/cytotoxic CX3CR1+ NK cell ratio towards the former in AO rats, so it was less favorable in aged AO rats exhibiting prolonged neurological deficit compared with their DA counterparts. The study showed strain and age differences in number of IFN-γ-producing NK cells in EAE rat dLNs, and suggested that their pathogenetic relevance depends on frequency and/or activity of other cells involved in CD4+ T cell (auto)immune response.
自然杀伤（NK）细胞可影响引流淋巴结（dLNs）中树突状细胞（DC）介导的CD4+淋巴细胞启动，并控制致脑炎性CD4+T淋巴细胞对脊髓（SC）的浸润，从而调节实验性自身免疫性脑脊髓炎（EAE，多发性硬化模型）。本研究检测了NK细胞对暗褐鼠（DA）（EAE易感性随年龄增长而降低）和白化牛津鼠（AO）（随年龄增长易患EAE）EAE发病年龄相关差异的潜在作用。衰老增加了两种品系大鼠dLNs中的NK细胞数量。在AO大鼠中，而非DA大鼠中，衰老还增加了产生IFN-γ的NK细胞（对DC激活很重要）和活化/成熟DC的数量，从而增加了活化/成熟DC/常规Foxp3-CD4+细胞比例和活化的CD25+Foxp3-CD4+细胞数量。DA大鼠的衰老则降低了活化/成熟DC/常规Foxp3-CD4+细胞比例和活化的Foxp3-CD4+细胞数量。然而，髓鞘碱性蛋白（MBP）刺激的CD4+细胞增殖在年轻和老年AO大鼠的dLN细胞培养物中并无差异（因为较低的固有CD4+细胞增殖能力和更高的调节性CD25+Foxp3+CD4+淋巴细胞频率消除了更有利的活化/成熟DC/Foxp3-CD4+细胞比例），但在老年DA大鼠与年轻DA大鼠相比的dLN细胞培养物中较低。在脊髓水平，衰老使AO大鼠的Foxp3-CD4+/细胞毒性CX3CR1+NK细胞比例向Foxp3-CD4+细胞倾斜，因此与DA大鼠相比，表现出更长时间神经功能缺损的老年AO大鼠情况更不利。该研究显示了EAE大鼠dLNs中产生IFN-γ的NK细胞数量的品系和年龄差异，并表明它们的致病相关性取决于参与CD4+T细胞（自身）免疫反应的其他细胞的频率和/或活性。
