Adoptive therapy with amyloid-β specific regulatory T cells alleviates Alzheimer's disease

Abstract

Neuroinflammation is a primary feature of Alzheimer's disease (AD), for which an increasing number of drugs have been specifically developed. The present study aimed to define the therapeutic impact of a specific subpopulation of T cells that can suppress excessive inflammation in various immune and inflammatory disorders, namely, CD4 + CD25 + Foxp3 + regulatory T cells (Tregs). Methods: To generate A antigen-specific Tregs (A + Tregs), A 1-42 peptide was applied in vivo and subsequent in vitro splenocyte culture. After isolating Tregs by magnetic bead based purification method, A + Tregs were adoptively transferred into 3xTg-AD mice via tail vein injection. Therapeutic efficacy was confirmed with behavior test, Western blot, quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry staining (IHC). In vitro suppression assay was performed to evaluate the suppressive activity of A + Tregs using flow cytometry. Thy1.1 + Treg trafficking and distribution was analyzed to explore the infused Tregs migration into specific organs in an antigen-driven manner in AD mice. We further assessed cerebral glucose metabolism using 18 F-FDG-PET, an imaging approach for AD biological definition. Subsequently, we evaluated the migration of A + Tregs toward A activated microglia using live cell imaging, chemotaxis, antibody blocking and migration assay. Results: We showed that A-stimulated Tregs inhibited microglial proinflammatory activity and modulated the microglial phenotype via bystander suppression. Single adoptive transfer of A + Tregs was enough to induce amelioration of cognitive impairments, A accumulation, hyper-phosphorylation of tau, and neuroinflammation during AD pathology. Moreover, A-specific Tregs effectively inhibited inflammation in primary microglia induced by A exposure. It may indicate bystander suppression in which A-specific Tregs promote immune tolerance by secreting cytokines to modulate immune responses during neurodegeneration. Conclusions: The administration of A antigen-specific regulatory T cells may represent a new cellular therapeutic strategy for AD that acts by modulating the inflammatory status in AD.