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

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 18 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. 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.

Blocking microglial proliferation by CSF-1R inhibitor does not alter the neuroprotective effects of adoptive regulatory T cells in 3xTg Alzheimer's disease mice

“…In our recently published data, we attempted depletion of adoptively transferred Tregs using the diphtheria toxin in DEpletion of REGulatory T cells (DEREG) mice, and found that adoptively transferred Tregs must survive for more than 7 days to induce neuroprotective effects [24]. In the current study, we tracked adoptively transferred Tregs in several tissues.…”

Molecular and cognitive signatures of ageing partially restored through synthetic delivery of IL2 to the brain

“…The results have, however, been inconsistent across models and with different modalities of treatment. For example, in AD, direct cell therapy with Tregs (Baek et al , 2016 ; Faridar et al , 2022 ; Yang et al , 2022 ) has given beneficial effects, although other studies have shown the reverse (Baruch et al , 2015 ; Yang et al , 2020 ), while treatment with IL2 has given conflicting results, depending on the AD model, ranging from protective (Baek et al , 2016 ; Alves et al , 2017 ) to minor (Dansokho et al , 2016 ) or no effect (preprint: Yshii et al , 2022a ). In PD models, a number of different Treg‐based treatments have been beneficial, including direct cell transfer (Reynolds et al , 2007 ; Huang et al , 2020 ; Markovic et al , 2022 ), using bee venom phospholipase A2 to induce Treg formation, superagonist anti‐CD28 antibodies to expand them (Badr et al , 2022 ) or vasoactive intestinal peptide receptor‐2 (VIPR2) peptide agonist to enhance activity (Mosley et al , 2019 ).…”

The association of microbial infection and adaptive immune cell activation in Alzheimer’s disease

“…As described above Tregs can play an important immune-modulatory role that contributes to AD pathology. Recent studies have suggested that Tregs can potentially be neuroprotective and can suppress excessive microglia activation and inflammation seen in AD brains [ 156 , 157 ]. These studies took an approach that examines what impact the adoptive transfer of in vitro expanded Tregs has on AD pathology using AD mice.…”

“…These studies took an approach that examines what impact the adoptive transfer of in vitro expanded Tregs has on AD pathology using AD mice. Tregs were either isolated from mouse splenocyte cultures and expanded using Aβ1-42 peptide to ensure antigen-specific Tregs were expanded [ 157 ], or were derived from human PBMC cultures and expanded for 24 days [ 156 ]. Expanded mouse Tregs were transferred into 3xTG AD mice where a noted reduction in microglial activation was seen with an associated amelioration of cognitive impairment [ 157 ].…”

“…Tregs were either isolated from mouse splenocyte cultures and expanded using Aβ1-42 peptide to ensure antigen-specific Tregs were expanded [ 157 ], or were derived from human PBMC cultures and expanded for 24 days [ 156 ]. Expanded mouse Tregs were transferred into 3xTG AD mice where a noted reduction in microglial activation was seen with an associated amelioration of cognitive impairment [ 157 ]. Human Tregs were transferred into 5xFAD AD mice that were crossed with Rag2 deficient mice.…”