Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation.
Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation.
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DOI：
10.3389/fncel.2021.686340
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发表时间：
2021
影响因子：
5.3
通讯作者：
Lokensgard JR
中科院分区：
文献类型：
--
作者：
Prasad S;Sheng WS;Hu S;Chauhan P;Lokensgard JR
在静息嗜神经病毒抗原（Ag）特异性脑驻留记忆CD8 + T细胞（bTRM）重新激活后，可能通过快速释放IFN-γ对新生病毒Ag产生应答，从而驱动周围小胶质细胞中后续干扰素刺激的基因表达。通过这种机制，少量的适应性bTRM可能会放大对病毒再激活的反应，从而导致器官范围内的先天保护状态。随着时间的推移，这种全脑先天免疫激活可能具有累积的神经毒性和神经认知后果。我们以前已经表明，HIV-1 p24 Ag特异性bTRM持续存在于小鼠脑内使用异源的prime-CNS加强策略。在对Ag再刺激的反应中，这些bTRM显示快速和稳健的回忆反应，随后激活神经胶质细胞。在这项研究中，我们假设反复挑战病毒抗原（Ag）（模拟反复发作的病毒再激活）最终导致长期反应性神经胶质增生和神经毒性加重。为了解决这个问题，首先用表达HIV p24衣壳蛋白的腺病毒载体免疫小鼠，然后使用Pr55Gag/Env病毒样颗粒（HIV-VLP）进行CNS加强。在建立bTRM群体后[> 30天（d）]，然后使用免疫显性HIV-1 AI9 CD8 + T细胞表位肽对初免-CNS加强动物进行体内攻击以及再攻击（在攻击后14天）。在这些研究中，Ag再激发导致小胶质细胞活化标志物的表达延长和增殖反应增加，比激发组更长。在AI9再激发后7、14和30天观察到MHCII和PD-L1（活化标志物）以及Ki67（增殖标志物）的这种持续表达。此外，体内再激发导致诱导型一氧化氮合酶（iNOS）的持续产生，在再激发后7、14和30天观察到水平升高。有趣的是，与再激发组相比，激发动物中的iNOS表达显著降低。此外，与激发组相比，体内特异性Ag再激发产生较低水平的精氨酸酶（Arg）-1。总之，这些结果表明，反复Ag特异性刺激的适应性免疫反应导致累积失调的小胶质细胞活化。
Upon reactivation of quiescent neurotropic viruses antigen (Ag)-specific brain resident-memory CD8+ T-cells (bTRM) may respond to de novo-produced viral Ag through the rapid release of IFN-γ, which drives subsequent interferon-stimulated gene expression in surrounding microglia. Through this mechanism, a small number of adaptive bTRM may amplify responses to viral reactivation leading to an organ-wide innate protective state. Over time, this brain-wide innate immune activation likely has cumulative neurotoxic and neurocognitive consequences. We have previously shown that HIV-1 p24 Ag-specific bTRM persist within the murine brain using a heterologous prime-CNS boost strategy. In response to Ag restimulation, these bTRM display rapid and robust recall responses, which subsequently activate glial cells. In this study, we hypothesized that repeated challenges to viral antigen (Ag) (modeling repeated episodes of viral reactivation) culminate in prolonged reactive gliosis and exacerbated neurotoxicity. To address this question, mice were first immunized with adenovirus vectors expressing the HIV p24 capsid protein, followed by a CNS-boost using Pr55Gag/Env virus-like particles (HIV-VLPs). Following the establishment of the bTRM population [>30 days (d)], prime-CNS boost animals were then subjected to in vivo challenge, as well as re-challenge (at 14 d post-challenge), using the immunodominant HIV-1 AI9 CD8+ T-cell epitope peptide. In these studies, Ag re-challenge resulted in prolonged expression of microglial activation markers and an increased proliferative response, longer than the challenge group. This continued expression of MHCII and PD-L1 (activation markers), as well as Ki67 (proliferative marker), was observed at 7, 14, and 30 days post-AI9 re-challenge. Additionally, in vivo re-challenge resulted in continued production of inducible nitric oxide synthase (iNOS) with elevated levels observed at 7, 14 and 30 days post re-challenge. Interestingly, iNOS expression was significantly lower among challenged animals when compared to re-challenged groups. Furthermore, in vivo specific Ag re-challenge produced lower levels of arginase (Arg)-1 when compared with the challenged group. Taken together, these results indicate that repeated Ag-specific stimulation of adaptive immune responses leads to cumulative dysregulated microglial cell activation.
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影响因子：
12.8
作者：
Kim, Tae-Shin;Shin, Eui-Cheol
通讯作者：
Shin, Eui-Cheol
病毒感染通过激活表达双重 TCR 的 CD8+ T 细胞触发中枢神经系统自身免疫。
影响因子：
30.5
作者：
Ji, Qingyong;Perchellet, Antoine;Goverman, Joan M.
通讯作者：
Goverman, Joan M.
影响因子：
5
作者：
Cheeran, Maxim C. -J.;Hu, Shuxian;Lokensgard, James R.
通讯作者：
Lokensgard, James R.
影响因子：
6.7
作者：
Doll, Jessica R.;Hoebe, Kasper;Sawtell, Nancy M.
通讯作者：
Sawtell, Nancy M.
影响因子：
5.4
作者：
Marten, NW;Stohlman, SA;Bergmann, CC
通讯作者：
Bergmann, CC