| First Author | Yang H | Year | 2022 |
| Journal | Theranostics | Volume | 12 |
| Issue | 18 | Pages | 7668-7680 |
| PubMed ID | 36451854 | Mgi Jnum | J:348479 |
| Mgi Id | MGI:7397809 | Doi | 10.7150/thno.75965 |
| Citation | Yang H, et al. (2022) Adoptive therapy with amyloid-beta specific regulatory T cells alleviates Alzheimer's disease. Theranostics 12(18):7668-7680 |
| abstractText | 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 Abeta antigen-specific Tregs (Abeta(+) Tregs), Abeta 1-42 peptide was applied in vivo and subsequent in vitro splenocyte culture. After isolating Tregs by magnetic bead based purification method, Abeta(+) 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 Abeta(+) 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 Abeta(+) Tregs toward Abeta activated microglia using live cell imaging, chemotaxis, antibody blocking and migration assay. Results: We showed that Abeta-stimulated Tregs inhibited microglial proinflammatory activity and modulated the microglial phenotype via bystander suppression. Single adoptive transfer of Abeta(+) Tregs was enough to induce amelioration of cognitive impairments, Abeta accumulation, hyper-phosphorylation of tau, and neuroinflammation during AD pathology. Moreover, Abeta-specific Tregs effectively inhibited inflammation in primary microglia induced by Abeta exposure. It may indicate bystander suppression in which Abeta-specific Tregs promote immune tolerance by secreting cytokines to modulate immune responses during neurodegeneration. Conclusions: The administration of Abeta antigen-specific regulatory T cells may represent a new cellular therapeutic strategy for AD that acts by modulating the inflammatory status in AD. |
