Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation
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 mechani...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-08-01
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| Series: | Frontiers in Cellular Neuroscience |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fncel.2021.686340/full |
| _version_ | 1819081299017596928 |
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| author | Sujata Prasad Wen S. Sheng Shuxian Hu Priyanka Chauhan James R. Lokensgard |
| author_facet | Sujata Prasad Wen S. Sheng Shuxian Hu Priyanka Chauhan James R. Lokensgard |
| author_sort | Sujata Prasad |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-21T19:58:34Z |
| format | Article |
| id | doaj.art-d76853a23004469fbd8d83fbb15f5763 |
| institution | Directory Open Access Journal |
| issn | 1662-5102 |
| language | English |
| last_indexed | 2024-12-21T19:58:34Z |
| publishDate | 2021-08-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Cellular Neuroscience |
| spelling | doaj.art-d76853a23004469fbd8d83fbb15f57632022-12-21T18:52:02ZengFrontiers Media S.A.Frontiers in Cellular Neuroscience1662-51022021-08-011510.3389/fncel.2021.686340686340Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen StimulationSujata PrasadWen S. ShengShuxian HuPriyanka ChauhanJames R. LokensgardUpon 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.https://www.frontiersin.org/articles/10.3389/fncel.2021.686340/fullviral reactivationmicroglianeurotoxicityreactive gliosisresident memory T-cellsimmune activation |
| spellingShingle | Sujata Prasad Wen S. Sheng Shuxian Hu Priyanka Chauhan James R. Lokensgard Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation Frontiers in Cellular Neuroscience viral reactivation microglia neurotoxicity reactive gliosis resident memory T-cells immune activation |
| title | Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation |
| title_full | Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation |
| title_fullStr | Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation |
| title_full_unstemmed | Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation |
| title_short | Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation |
| title_sort | dysregulated microglial cell activation and proliferation following repeated antigen stimulation |
| topic | viral reactivation microglia neurotoxicity reactive gliosis resident memory T-cells immune activation |
| url | https://www.frontiersin.org/articles/10.3389/fncel.2021.686340/full |
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