Amyloid-[beta] specific regulatory T cells attenuate Alzheimer's disease pathobiology in APP/PS1 mice

• Published in: Molecular neurodegeneration 2023-12, Vol.18 (1)
• Main Authors: Yeapuri, Pravin, Machhi, Jatin, Lu, Yaman, Abdelmoaty, Mai Mohamed, Kadry, Rana, Patel, Milankumar, Bhattarai, Shaurav, Lu, Eugene, Namminga, Krista L, Olson, Katherine E, Foster, Emma G, Mosley, R. Lee, Gendelman, Howard E
• Format: Article
• Language: English
• Subjects: Alzheimer's disease; Amyloid beta-protein; Antigens; Brain; Ethylenediaminetetraacetic acid; Genetic engineering; Health aspects; Immunotherapy; Scientific equipment and supplies industry; T cells
• ISSN: 1750-1326; 1750-1326
• DOI: 10.1186/s13024-023-00692-7

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 (A[beta]) antigen specificity was conferred to Treg responses by engineering the T cell receptor (TCR) specific for A[beta] (TCR.sub.A.sub.[beta]). The TCR.sub.Ab were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCR.sub.A[beta] (TCR.sub.A[beta] -Tregs) to reduce A[beta] burden, transform effector to regulatory cells, and reverse disease-associated neurotoxicity proved beneficial in an animal model of Alzheimer's disease. Methods TCR.sub.A.sub.[beta] -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCR.sub.Ab identified from A[beta] reactive Teff monoclones. Antigen specificity was confirmed by MHC-A[beta]-tetramer staining. Adoptive transfer of TCR.sub.A[beta]-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.sub.A[beta]-Tregs expressed an A[beta]-specific TCR. Adoptive transfer of TCR.sub.A[beta]-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. .sup.18F-fluorodeoxyglucose radiolabeled TCR.sub.A[beta]-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. Conclusions TCR.sub.A[beta]-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 Keywords: Treg cell therapy, Alzheimer's disease, Immunotherapy, Antigen specific, T cell receptor, Amyloid beta