A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, Kuopio, Finland.
Neuroscience Center, Helsinki Institute of Life Science (HiLIFE), University of Helsinki, Helsinki, Finland.
Front Immunol. 2021 Jan 27;11:559810. doi: 10.3389/fimmu.2020.559810. eCollection 2020.
The recently discovered meningeal lymphatic vessels (mLVs) have been proposed to be the missing link between the immune and the central nervous system. The role of mLVs in modulating the neuro-immune response following a traumatic brain injury (TBI), however, has not been analyzed. Parenchymal T lymphocyte infiltration has been previously reported as part of secondary events after TBI, suggestive of an adaptive neuro-immune response. The phenotype of these cells has remained mostly uncharacterized. In this study, we identified subpopulations of T cells infiltrating the perilesional areas 30 days post-injury (an early-chronic time point). Furthermore, we analyzed how the lack of mLVs affects the magnitude and the type of T cell response in the brain after TBI.
TBI was induced in K14-VEGFR3-Ig transgenic (TG) mice or in their littermate controls (WT; wild type), applying a controlled cortical impact (CCI). One month after TBI, T cells were isolated from cortical areas ipsilateral or contralateral to the trauma and from the spleen, then characterized by flow cytometry. Lesion size in each animal was evaluated by MRI.
In both WT and TG-CCI mice, we found a prominent T cell infiltration in the brain confined to the perilesional cortex and hippocampus. The majority of infiltrating T cells were cytotoxic CD8+ expressing a CD44CD69+ phenotype, suggesting that these are effector resident memory T cells. K14-VEGFR3-Ig mice showed a significant reduction of infiltrating CD4+ T lymphocytes, suggesting that mLVs could be involved in establishing a proper neuro-immune response. Extension of the lesion (measured as lesion volume from MRI) did not differ between the genotypes. Finally, TBI did not relate to alterations in peripheral circulating T cells, as assessed one month after injury.
Our results are consistent with the hypothesis that mLVs are involved in the neuro-immune response after TBI. We also defined the resident memory CD8+ T cells as one of the main population activated within the brain after a traumatic injury.
最近发现脑膜淋巴管（mLVs）是免疫和中枢神经系统之间缺失的连接。然而，mLVs 在调节创伤性脑损伤（TBI）后的神经免疫反应中的作用尚未被分析。脑实质 T 淋巴细胞浸润先前被报道为 TBI 后二级事件的一部分，提示存在适应性神经免疫反应。这些细胞的表型特征大多尚未确定。在这项研究中，我们鉴定了损伤后 30 天（早期慢性时间点）浸润损伤周围区域的 T 细胞亚群。此外，我们分析了缺乏 mLVs 如何影响 TBI 后大脑中 T 细胞反应的程度和类型。
在 K14-VEGFR3-Ig 转基因（TG）小鼠或其同窝对照（WT；野生型）中诱导 TBI，应用皮质撞击（CCI）。TBI 后 1 个月，从创伤对侧或同侧皮质区和脾脏中分离 T 细胞，然后通过流式细胞术进行鉴定。每只动物的损伤大小通过 MRI 进行评估。
在 WT 和 TG-CCI 小鼠中，我们发现 T 细胞浸润明显局限于损伤周围皮质和海马区。浸润 T 细胞的大多数为表达 CD44CD69+表型的细胞毒性 CD8+，提示这些是效应驻留记忆 T 细胞。K14-VEGFR3-Ig 小鼠显示浸润的 CD4+T 淋巴细胞显著减少，提示 mLVs 可能参与建立适当的神经免疫反应。两种基因型之间的病变扩展（通过 MRI 测量的损伤体积）没有差异。最后，TBI 与受伤后一个月外周循环 T 细胞的变化无关。
我们的结果与 mLVs 参与 TBI 后神经免疫反应的假说一致。我们还将驻留记忆 CD8+T 细胞定义为创伤后大脑中激活的主要细胞群之一。
