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

• Published in: Theranostics 2022, Vol.12 (18), p.7668-7680
• Main Authors: Yang, HyeJin, Park, Seon-Young, Baek, Hyunjung, Lee, Chanju, Chung, Geehoon, Liu, Xiao, Lee, Ji Hwan, Kim, Byungkyu, Kwon, Minjin, Choi, Hyojung, Kim, Hyung Joon, Kim, Jae Yoon, Kim, Younsub, Lee, Ye-Seul, Lee, Gaheon, Kim, Sun Kwang, Kim, Jin Su, Chang, Young-Tae, Jung, Woo Sang, Kim, Kyung Hwa, Bae, Hyunsu
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - therapy; Alzheimer's disease; Amyloid beta-Peptides; Animals; Antibodies; Antigens; Brain; Cognitive Dysfunction; Experiments; Immunotherapy; Inflammation - therapy; Laboratories; Lymphocytes; Mice; Neurodegeneration; Peptides; Research Paper; Spleen; T-Lymphocytes, Regulatory
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.75965

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