Adoptive therapy with amyloid-β specific regulatory T cells alleviates Alzheimer's disease
Hyejin Yang, Seon‐Young Park, Hyunjung Baek, Chanju Lee, Geehoon Chung, Xiao Liu, Ji Hwan Lee, Byung Kyu Kim, Minjin Kwon, Hyo-Jung Choi, Hyung Joon Kim, Jae Yoon Kim, Younsub Kim, Ye‐Seul Lee, Gaheon Lee, Sun Kwang Kim, Jin Su Kim, Young‐Tae Chang, Woo Sang Jung, Kyung Hwa Kim, Hyunsu Bae
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.