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

Sujata Prasad; Amar Singh; Shuxian Hu; Wen S Sheng; Priyanka Chauhan; James R Lokensgard

doi:10.1016/j.isci.2023.106628

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

iScience. 2023 Apr 8;26(5):106628. doi: 10.1016/j.isci.2023.106628. eCollection 2023 May 19.

Authors

Sujata Prasad¹, Amar Singh^{1

2}, Shuxian Hu¹, Wen S Sheng¹, Priyanka Chauhan¹, James R Lokensgard¹

Affiliations

¹ Neurovirology Laboratory, Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA.
² Schulze Diabetes Institute Department of Surgery, University of Minnesota, Minneapolis, MN 55455, USA.

Abstract

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_RM), within brain: bT_RM. Reactivation of bT_RM 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.

Keywords: Components of the immune system; Immunology; Neuroscience.