Center for Neurobiology & Vaccine Development, Ophthalmology Research, Department of Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA.
Department of Biology, Pomona College, Claremont, California, USA.
J Virol. 2021 Jan 28;95(4). doi: 10.1128/JVI.01934-20.
We recently reported the role of type 2 innate lymphoid cells (ILC2s) in central nervous system (CNS) demyelination using a model of CNS demyelination involving recombinant herpes simplex virus 1 (HSV-1) that constitutively expresses mouse interleukin 2 (HSV-IL-2). In this investigation, we studied how ILC2s respond to HSV-IL-2 at the cellular level using cytokine and gene expression profiling. ILC2s infected with HSV-IL-2 expressed higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-5, IL-6, IL-13, IP-10, MIP-2, and RANTES, which include proinflammatory cytokines, than did those infected with parental control virus. In contrast, T2 cytokines IL-4 and IL-9, which are typically expressed by ILC2s, were not induced upon HSV-IL-2 infection. Transcriptome sequencing (RNA-seq) analysis of HSV-IL-2 infected ILC2s showed significant upregulation of over 350 genes and downregulation of 157 genes compared with parental virus-infected ILC2s. Gene Ontology (GO) term analysis indicated that genes related to "mitosis" and "inflammatory response" were among the upregulated genes, suggesting that HSV-IL-2 infection drives the excessive proliferation and atypical inflammatory response of ILC2s. This change in ILC2 activation state could underlie the pathology of demyelinating diseases. Innate lymphocytes have plasticity and can change functionality; type 2 innate lymphoid cells (ILC2s) can convert to ILC1 or ILC3 cells or change their activation state to produce IL-17 or IL-10 depending on environmental cues. In this study, we investigated the gene and cytokine profiles of ILC2s, which play a major role in HSV-IL-2-induced CNS demyelination. ILC2s infected with HSV-IL-2 displayed a massive remodeling of cellular state. Additionally, ILC2s infected with HSV-IL-2 differed from those infected with parental HSV in cellular and viral gene expression profiles and in cytokine/chemokine induction, and they displayed enhanced activation and proinflammatory responses. These changes in ILC2 activation state could underlie the pathology of demyelinating diseases. These results also highlight the possible importance of pathogens as environmental cues to modify innate lymphocyte functionalities.
我们最近报道了 2 型固有淋巴细胞（ILC2）在中枢神经系统（CNS）脱髓鞘中的作用，该模型涉及表达小鼠白细胞介素 2（HSV-IL-2）的重组单纯疱疹病毒 1（HSV-1）。在这项研究中，我们使用细胞因子和基因表达谱研究了 ILC2 如何在细胞水平上对 HSV-IL-2 做出反应。感染 HSV-IL-2 的 ILC2 表达更高水平的粒细胞-巨噬细胞集落刺激因子（GM-CSF）、IL-5、IL-6、IL-13、IP-10、MIP-2 和 RANTES，包括促炎细胞因子，而感染亲本对照病毒的 ILC2 则没有。相反，通常由 ILC2 表达的 T2 细胞因子 IL-4 和 IL-9 在 HSV-IL-2 感染后并未被诱导。与感染亲本病毒的 ILC2 相比，感染 HSV-IL-2 的 ILC2 的转录组测序（RNA-seq）分析显示超过 350 个基因的显著上调和 157 个基因的下调。基因本体论（GO）术语分析表明，与“有丝分裂”和“炎症反应”相关的基因是上调基因之一，表明 HSV-IL-2 感染导致 ILC2 的过度增殖和非典型炎症反应。这种 ILC2 激活状态的变化可能是脱髓鞘疾病发病机制的基础。先天淋巴细胞具有可塑性，可以改变功能；2 型固有淋巴细胞（ILC2）可以根据环境线索转化为 ILC1 或 ILC3 细胞，或改变其激活状态以产生 IL-17 或 IL-10。在这项研究中，我们研究了在 HSV-IL-2 诱导的中枢神经系统脱髓鞘中起主要作用的 ILC2 的基因和细胞因子谱。感染 HSV-IL-2 的 ILC2 显示出细胞状态的大规模重塑。此外，感染 HSV-IL-2 的 ILC2 与感染亲本 HSV 的 ILC2 在细胞和病毒基因表达谱以及细胞因子/趋化因子诱导方面存在差异，并且它们表现出增强的激活和促炎反应。ILC2 激活状态的这些变化可能是脱髓鞘疾病发病机制的基础。这些结果还强调了病原体作为改变先天淋巴细胞功能的环境线索的重要性。
