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

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 (TCR A β ). The TCR Ab were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCR Aβ (TCR Aβ -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 TCR A β -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCR Ab identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCR Aβ -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 Aβ -Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCR Aβ -Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. 18 F-fluorodeoxyglucose radiolabeled TCR Aβ -Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. Conclusions TCR Aβ -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