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Abstract
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 Aβ antigen-specific Tregs (Aβ+ Tregs), Aβ 1-42 peptide was applied in vivo and subsequent in vitro 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). In vitro 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 18F-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. Results: 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. Conclusions: 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.

Affiliations

HyeJin Yang 1, Seon-Young Park 1, Hyunjung Baek 1, Chanju Lee 1 2, Geehoon Chung 1, Xiao Liu 3, Ji Hwan Lee 1, Byungkyu Kim 1, Minjin Kwon 1, Hyojung Choi 1, Hyung Joon Kim 4, Jae Yoon Kim 4, Younsub Kim 5, Ye-Seul Lee 5, Gaheon Lee 6, Sun Kwang Kim 1, Jin Su Kim 7, Young-Tae Chang 3 8, Woo Sang Jung 9, Kyung Hwa Kim 6, Hyunsu Bae 1
1Department of Physiology, College of Korean Medicine, Kyung Hee University, 26-6 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02453, Korea.
2Cancer Immunology Branch, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Korea.
3Department of Chemistry, Pohang University of Science and Technology, Pohang 37673, Korea.
4Institute of Life Science & Biotechnology, VT Bio. Co., Ltd. 3 rd FL, 16 Samseong-ro 76-gil, Gangnam-gu, Seoul 06185, Korea.
5Department of Anatomy and Acupoint, College of Korean Medicine, Gachon University, Seongnam 13120, Korea.
6Department of Health Sciences, The Graduate School of Dong-A University, 840 Hadan-dong, Saha-gu, Busan 49315, Korea.
7Division of RI Application, Korea Institute Radiological and Medical Sciences, 75 Nowon-ro, Nowon-Gu, Seoul 01812, Korea.
8Center for Self-assembly and Complexity, Institute for Basic Science (IBS), Pohang 37673, Korea.
9Stroke center, Kyung Hee University, 26-6 Kyungheedae-ro, Dongdaemoon-gu, Seoul 02453, Korea.