Amyloid-β specific regulatory T cells attenuate Alzheimer’s disease pathobiology in APP/PS1 mice

Pravin Yeapuri, Jatin Machhi, Yaman Lu, Mai Mohamed Abdelmoaty, Rana Kadry, Milankumar Patel, Shaurav Bhattarai, Eugene Lu, Krista L. Namminga, Katherine E. Olson, Emma G. Foster, R. Lee Mosley, Howard E. Gendelman

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Background: Regulatory T cells (Tregs) maintain immune tolerance. While Treg-mediated neuroprotective activities are now well-accepted, the lack of defined antigen specificity limits their therapeutic potential. This is notable for neurodegenerative diseases where cell access to injured brain regions is required for disease-specific therapeutic targeting and improved outcomes. To address this need, amyloid-beta (Aβ) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for Aβ (TCRAβ). The TCRAb were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCR (TCR -Tregs) to reduce Aβ burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer’s disease. Methods: TCRAβ -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCRAb identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCR-Tregs to mice expressing a chimeric mouse-human amyloid precursor protein and a mutant human presenilin-1 followed measured behavior, immune, and immunohistochemical outcomes. Results: TCR-Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCR-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18F-fluorodeoxyglucose radiolabeled TCR-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. Conclusions: TCR-Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD. Graphical Abstract: [Figure not available: see fulltext.]

Original languageEnglish (US)
Article number97
JournalMolecular neurodegeneration
Volume18
Issue number1
DOIs
StatePublished - Dec 2023

Keywords

  • Alzheimer’s disease
  • Amyloid beta
  • Antigen specific
  • Immunotherapy
  • T cell receptor
  • Treg cell therapy

ASJC Scopus subject areas

  • Molecular Biology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

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