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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 (bT(RM)) 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 mecha...

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Autores principales: Prasad, Sujata, Sheng, Wen S., Hu, Shuxian, Chauhan, Priyanka, Lokensgard, James R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383069/
https://www.ncbi.nlm.nih.gov/pubmed/34447297
http://dx.doi.org/10.3389/fncel.2021.686340
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author Prasad, Sujata
Sheng, Wen S.
Hu, Shuxian
Chauhan, Priyanka
Lokensgard, James R.
author_facet Prasad, Sujata
Sheng, Wen S.
Hu, Shuxian
Chauhan, Priyanka
Lokensgard, James R.
author_sort Prasad, Sujata
collection PubMed
description Upon reactivation of quiescent neurotropic viruses antigen (Ag)-specific brain resident-memory CD8+ T-cells (bT(RM)) 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 bT(RM) 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 bT(RM) persist within the murine brain using a heterologous prime-CNS boost strategy. In response to Ag restimulation, these bT(RM) 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 bT(RM) 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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spelling pubmed-83830692021-08-25 Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation Prasad, Sujata Sheng, Wen S. Hu, Shuxian Chauhan, Priyanka Lokensgard, James R. Front Cell Neurosci Cellular Neuroscience Upon reactivation of quiescent neurotropic viruses antigen (Ag)-specific brain resident-memory CD8+ T-cells (bT(RM)) 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 bT(RM) 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 bT(RM) persist within the murine brain using a heterologous prime-CNS boost strategy. In response to Ag restimulation, these bT(RM) 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 bT(RM) 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. Frontiers Media S.A. 2021-08-10 /pmc/articles/PMC8383069/ /pubmed/34447297 http://dx.doi.org/10.3389/fncel.2021.686340 Text en Copyright © 2021 Prasad, Sheng, Hu, Chauhan and Lokensgard. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cellular Neuroscience
Prasad, Sujata
Sheng, Wen S.
Hu, Shuxian
Chauhan, Priyanka
Lokensgard, James R.
Dysregulated Microglial Cell Activation and Proliferation Following Repeated Antigen Stimulation
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 Cellular Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8383069/
https://www.ncbi.nlm.nih.gov/pubmed/34447297
http://dx.doi.org/10.3389/fncel.2021.686340
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