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

초록

Rationale: 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 AP antigen-specific Tregs (AP+ Tregs), AP 1-42 peptide was applied in vivo and subsequent in vitro splenocyte culture. After isolating Tregs by magnetic bead based purification method, AP+ 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 AP+ 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 18F-FDG-PET, an imaging approach for AD biological definition. Subsequently, we evaluated the migration of AP+ Tregs toward AP activated microglia using live cell imaging, chemotaxis, antibody blocking and migration assay.Results: We showed that AP-stimulated Tregs inhibited microglial proinflammatory activity and modulated the microglial phenotype via bystander suppression. Single adoptive transfer of AP+ Tregs was enough to induce amelioration of cognitive impairments, AP accumulation, hyper-phosphorylation of tau, and neuroinflammation during AD pathology. Moreover, AP-specific Tregs effectively inhibited inflammation in primary microglia induced by AP exposure. It may indicate bystander suppression in which AP-specific Tregs promote immune tolerance by secreting cytokines to modulate immune responses during neurodegeneration.Conclusions: The administration of AP antigen-specific regulatory T cells may represent a new cellular therapeutic strategy for AD that acts by modulating the inflammatory status in AD.

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