Molecular Neurotrauma and Haemostasis, Australian Centre for Blood Diseases, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC 3004, Australia.
Cell Rep. 2019 Oct 29;29(5):1178-1191.e6. doi: 10.1016/j.celrep.2019.09.046.
Traumatic brain injury (TBI) leaves many survivors with long-term disabilities. A prolonged immune response in the brain may cause neurodegeneration, resulting in chronic neurological disturbances. In this study, using a TBI mouse model, we correlate changes in the local immune response with neurodegeneration/neurological dysfunction over an 8-month period. Flow cytometric analysis reveals a protracted increase in effector/memory CD8 T cells (expressing granzyme B) in the injured brain. This precedes interleukin-17CD4 T cell infiltration and is associated with progressive neurological/motor impairment, increased circulating brain-specific autoantibodies, and myelin-related pathology. Genetic deficiency or pharmacological depletion of CD8 T cells, but not depletion of CD4 T cells, improves neurological outcomes and produces a neuroprotective Th2/Th17 immunological shift, indicating a persistent detrimental role for cytotoxic T cells post-TBI. B cell deficiency results in severe neurological dysfunction and a heightened immune reaction. Targeting these adaptive immune cells offers a promising approach to improve recovery following TBI.
创伤性脑损伤（TBI）使许多幸存者长期残疾。大脑中持续的免疫反应可能导致神经退行性变，从而导致慢性神经功能障碍。在这项研究中，我们使用 TBI 小鼠模型，将局部免疫反应的变化与 8 个月期间的神经退行性变/神经功能障碍相关联。流式细胞术分析显示，损伤大脑中的效应/记忆 CD8 T 细胞（表达颗粒酶 B）持续增加。这先于白细胞介素 17 CD4 T 细胞浸润，并与进行性神经/运动功能障碍、循环中脑特异性自身抗体增加和髓鞘相关病理学有关。CD8 T 细胞的基因缺失或药物耗竭，但不是 CD4 T 细胞的耗竭，可改善神经功能结局并产生神经保护的 Th2/Th17 免疫转变，表明细胞毒性 T 细胞在 TBI 后持续发挥有害作用。B 细胞缺失导致严重的神经功能障碍和增强的免疫反应。靶向这些适应性免疫细胞为改善 TBI 后的恢复提供了一种有前途的方法。
