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Amyloid-β specific regulatory T cells attenuate Alzheimer's disease pathobiology in APP/PS1 mice.
- Source :
- Molecular Neurodegeneration; 12/18/2023, Vol. 18 Issue 1, p1-22, 22p
- Publication Year :
- 2023
-
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<subscript>A</subscript><subscript>β</subscript>). The TCR<subscript>Ab</subscript> were developed from disease-specific T cell effector (Teff) clones. The ability of Tregs expressing a transgenic TCR<subscript>Aβ</subscript> (TCR<subscript>Aβ</subscript> -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<subscript>A</subscript><subscript>β</subscript> -Tregs were generated by CRISPR-Cas9 knockout of endogenous TCR and consequent incorporation of the transgenic TCR<subscript>Ab</subscript> identified from Aβ reactive Teff monoclones. Antigen specificity was confirmed by MHC-Aβ-tetramer staining. Adoptive transfer of TCR<subscript>Aβ</subscript>-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<subscript>Aβ</subscript>-Tregs expressed an Aβ-specific TCR. Adoptive transfer of TCR<subscript>Aβ</subscript>-Tregs led to sustained immune suppression, reduced microglial reaction, and amyloid loads. <superscript>18</superscript>F-fluorodeoxyglucose radiolabeled TCR<subscript>Aβ</subscript>-Treg homed to the brain facilitating antigen specificity. Reduction in amyloid load was associated with improved cognitive functions. Conclusions: TCR<subscript>Aβ</subscript>-Tregs reduced amyloid burden, restored brain homeostasis, and improved learning and memory, supporting the increased therapeutic benefit of antigen specific Treg immunotherapy for AD. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 17501326
- Volume :
- 18
- Issue :
- 1
- Database :
- Complementary Index
- Journal :
- Molecular Neurodegeneration
- Publication Type :
- Academic Journal
- Accession number :
- 174298299
- Full Text :
- https://doi.org/10.1186/s13024-023-00692-7