Prasad Sujata, Singh Amar, Hu Shuxian, Sheng Wen S, Chauhan Priyanka, Lokensgard James R
Neurovirology Laboratory, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
Schulze Diabetes Institute Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.
iScience. 2023 Apr 8;26(5):106628. doi: 10.1016/j.isci.2023.106628. eCollection 2023 May 19.
This study was undertaken to investigate the role of CD4+FoxP3+ regulatory T cells (Tregs) in regulating neuroinflammation during viral Ag-challenge and re-challenge. CD8 lymphocytes persisting within tissues are designated tissue-resident memory T cells (T), within brain: bT. Reactivation of bT with T cell epitope peptides generates rapid antiviral recall, but repeated stimulation leads to cumulative dysregulation of microglial activation, proliferation, and prolonged neurotoxic mediator production. Here, we show Tregs were recruited into murine brains following prime-CNS boost, but displayed altered phenotypes following repeated Ag-challenge. In response to repeated Ag, brain Tregs (bTregs) displayed inefficient immunosuppressive capacity, along with reduced expression of suppression of tumorigenicity 2 (ST2) and amphiregulin (Areg). Areg treatment revealed reduced production of neurotoxic mediators such as iNOS, IL-6, and IL-1β, and decreased microglial activation and proliferation. Taken together, these data indicate bTregs display an unstable phenotype and fail to control reactive gliosis in response to repeated Ag-challenge.
本研究旨在探讨CD4+FoxP3+调节性T细胞（Tregs）在病毒抗原攻击和再次攻击期间调节神经炎症中的作用。持续存在于组织中的CD8淋巴细胞被称为组织驻留记忆T细胞（T），在脑中为脑驻留记忆T细胞（bT）。用T细胞表位肽重新激活bT可产生快速的抗病毒回忆反应，但反复刺激会导致小胶质细胞激活、增殖的累积失调以及神经毒性介质产生时间延长。在此，我们发现初次中枢神经系统加强免疫后Tregs被招募到鼠脑，但在反复抗原攻击后其表型发生改变。响应反复抗原刺激，脑Tregs（bTregs）表现出低效的免疫抑制能力，同时肿瘤抑制因子2（ST2）和双调蛋白（Areg）的表达降低。Areg治疗显示神经毒性介质如诱导型一氧化氮合酶（iNOS）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β）的产生减少，小胶质细胞激活和增殖也减少。综上所述，这些数据表明bTregs表现出不稳定的表型，并且在反复抗原攻击时无法控制反应性胶质增生。
