Authors: Alireza Faridar, Aaron Thome, Weihua Zhao, Jason R Thonhoff, David Beers, Belen Pascual, Joseph C. Masdeu, Stanley Appel
Published: 2020-12-07
DOI: 10.1002/alz.039830
Source: Full article
AbstractBackgroundInflammation is a significant component of Alzheimer disease (AD) pathology. Chronically activated microglia release proinflammatory cytokines, mediate synaptic loss and exacerbate tau propagation. Regulatory T cells (Tregs) have been shown to suppress microglia‐mediated inflammation. We have previously found a failure in suppressive activity of Tregs at the clinical Alzheimer dementia stage. In this study we evaluate the potential of ex vivo expansion of AD Tregs to modify their immunophenotype and restore their function.Method10 patients with Alzheimer disease, 10 with mild cognitive impairment and 10 healthy controls were studied. Tregs were co‐cultured with responder T cells and proliferation was determined by 3H‐thymidine incorporation. In separate experiments, regulatory T cells were added to induced pluripotent stem cell‐derived pro‐inflammatory macrophages and changes in IL‐6/TNF‐a transcripts and protein levels were measured. Freshly isolated regulatory T cells were also expanded ex vivo in the presence of CD3/CD28 expander beads, interleukin‐2 (IL‐2) and rapamycin to promote their suppressive function. The immunophenotype of baseline and ex vivo expanded regulatory T cells from were also assessedResultThe suppressive function of regulatory T cells on responder T cell proliferation was compromised at the Alzheimer disease stage, compared with mild cognitive impairment and healthy controls. Tregs did not suppress proinflammatory macrophages at baseline. However, following ex vivo expansion, Treg suppression of responder T cell proliferation and pro‐inflammatory macrophage activation increased in both patients and controls. Ex vivo expanded Tregs expressed higher levels of immunoregulatory markers including CD25, FoxP3, Granzyme B and PD1. In further evaluation of underlying mechanism, these cells exerted their suppressive function on pro‐inflammatory macrophages through a contact‐mediated mode of action.ConclusionOur data demonstrates that the ex vivo expansion of dysfunctional Tregs alters their immunophenotype and enhance their suppressive function at the Alzheimer disease stage. Restoration of regulatory T cell function could be explored as a means to modulate the inflammatory status of Alzheimer disease.