Dysregulated brain regulatory T cells fail to control reactive gliosis following repeated antigen stimulation

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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 (TRM), within brain: bTRM. Reactivation of bTRM 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). Ex vivo 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.

Original languageEnglish (US)
Article number106628
Issue number5
StatePublished - May 19 2023

Bibliographical note

Funding Information:
This project was supported by award numbers NS-038836 from the National Institute of Neurological Disorders and Stroke ; and MH-066703 from the National Institute of Mental Health .

Publisher Copyright:
© 2023 The Author(s)


  • Components of the immune system
  • Immunology
  • Neuroscience


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