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

摘要： 两种不同细胞类型之间的融合是否会产生一种非传统的感染记忆？这会不会 杂交细胞是保护未来的流行病，还是促进神经退化和认知能力下降？病毒式地 在感染的小鼠中，我们偶然发现星形胶质细胞之间存在长时间的细胞融合， 中枢神经系统(CNS)中的主要胶质细胞类型，以及抗病毒CD8 T淋巴细胞(T细胞)，这是 上呼吸道感染后侵入中枢神经系统。值得注意的是，这些T细胞/星形胶质细胞杂交体保留了 星形胶质细胞的细胞结构，但维持只存在于T细胞基因组中的基因表达。而组织- 已知驻留记忆T细胞在感染后仍留在中枢神经系统，T细胞/星形胶质细胞融合代表 我们一直观察到的全新的细胞命运。这表明从T细胞转移的遗传物质 细胞可能代表了与星形胶质细胞反应性有关的一种普遍现象。组织学研究 人类大脑已经描述了中枢神经系统内的造血融合，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，包括那些引起 上呼吸道感染(URI)，直接感染或影响中枢神经系统，症状从轻微到 炎症会导致显性脑炎，并与认知改变和神经退化有关， 包括与流感和新冠肺炎有关的“大脑迷雾”。这些对大脑功能的不同影响很可能 在动物模型中，很容易观察到中枢神经系统基因表达的多因素但区域性变化。我们 假设T细胞/星形胶质细胞杂交代表了一种新的细胞类型，具有根深蒂固的记忆 导致炎症和神经退行性变过程的炎症。我们将建立参数 它管理星形胶质细胞和T细胞杂交的形成，并确定核心签名和生物学后果 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.