T cell/astrocyte fusions as a novel form of trained immunity to infection

摘要： 两种完全不同的细胞类型之间的融合会产生一种非传统的感染记忆吗？这是否 杂交细胞是预防未来流行病还是促进神经退化和认知能力下降？在virally 在感染的小鼠中，我们偶然发现星形胶质细胞之间存在长寿命的细胞融合， 中枢神经系统（CNS）中的主要神经胶质细胞类型和抗病毒CD 8 + T淋巴细胞（T细胞）， 在上呼吸道感染后浸润中枢神经系统。值得注意的是，这些T细胞/星形胶质细胞杂交体保留了T细胞的免疫原性。 星形胶质细胞的细胞结构，但维持仅存在于T细胞基因组中的基因表达。当组织- 已知常驻记忆T细胞在感染后保留在CNS中，T细胞/星形胶质细胞融合代表了免疫应答。 我们一直观察到的全新的细胞命运这表明T细胞的遗传物质转移 细胞可以代表与星形胶质细胞反应性相关的普遍现象。的组织学研究 人脑已经描述了CNS内的造血融合，特别是在炎症环境中，但 其驱动力、机制和影响尚不清楚。人类病原体，包括那些导致 上呼吸道感染（URI），直接感染或影响中枢神经系统，症状范围从轻度 从炎症到明显的脑炎，并与认知变化和神经退行性变有关， 包括与流感和新冠肺炎相关的“脑雾”。这些对大脑功能的不同影响可能是 在动物模型中容易观察到CNS基因表达的多因素但局部的改变。我们 假设T细胞/星形胶质细胞杂交体代表了一种新细胞类型， 导致炎症和神经退行性过程的炎症。我们将建立参数 控制星形胶质细胞和T细胞杂交体的形成，并识别出 感染驱动的细胞杂交对炎症和免疫过程的影响。

Abstract: Could fusion between two disparate cell types generate an unconventional memory of infection? Would this hybrid cell protect against tomorrow’s pandemics or promote neurodegeneration and cognitive decline? In virally infected mice, we serendipitously discovered the presence of long-lived cellular fusions between astrocytes, a major glial cell type in the central nervous system (CNS), and antiviral CD8+ T lymphocytes (T cells), which infiltrate the CNS following an upper airway infection. Remarkably, these T cell/astrocyte hybrids retain the cellular structure of an astrocyte but maintain gene expression only present in the T cell genome. While tissue- resident memory T cells are known to remain in the CNS after infection, T cell/astrocyte fusions represent an entirely novel cell fate that we consistently observe. This suggests that the transfer of genetic material from T cells could represent a widespread phenomenon associated with astrocyte reactivity. Histological studies of human brains have described hematopoietic fusions within the CNS, particularly in inflammatory settings, but the driving forces, mechanisms, and implications are unknown. Human pathogens, including those that cause upper respiratory infections (URI), directly infect or impact the CNS with symptoms ranging from mild inflammation to overt encephalitis and have been associated with cognitive changes and neurodegeneration, including “brain fog” associated with Influenza and Covid-19. These varying impacts on brain function are likely multifactorial but regional alterations in CNS gene expression are readily observed in animal models. We hypothesize that T cell/astrocyte hybrids represent a novel cell type possessing an engrained memory of inflammation that contributes to inflammatory and neurodegenerative processes. We will establish parameters that govern astrocyte and T cell hybrid formation and identify a core signature and biological consequences of infection-driven cell hybridization on inflammatory and immune processes.