Restoring regulatory T-cell dysfunction in Alzheimer's disease through ex vivo expansion. Issue 2 (20th July 2020)

• Record Type: Journal Article
• Authors: Faridar, Alireza; Thome, Aaron D; Zhao, Weihua; Thonhoff, Jason R; Beers, David R; Pascual, Belen; Masdeu, Joseph C; Appel, Stanley H
• Is Part Of: Brain communications. Volume 2:Issue 2(2020)
• Publication Date: 2020-07-20
• Subjects: regulatory T cells -- Alzheimer's disease -- inflammation -- immune system -- dementia; 616
• DOI: 10.1093/braincomms/fcaa112
• Languages: English
• ISSNs: 2632-1297

Abstract

Abstract: Inflammation is a significant component of Alzheimer's disease pathology. While neuroprotective microglia are important for containment/clearance of Amyloid plaques and maintaining neuronal survival, Alzheimer inflammatory microglia may play a detrimental role by eliciting tau pathogenesis and accelerating neurotoxicity. Regulatory T cells have been shown to suppress microglia-mediated inflammation. However, the role of regulatory T cells in ameliorating the proinflammatory immune response in Alzheimer's disease requires further investigation. Forty-six patients with Alzheimer disease, 42 with mild cognitive impairment and 41 healthy controls were studied. The phenotypes of peripheral regulatory T cells were assessed with multicolour flow cytometry. Regulatory T cells were co-cultured with responder T cells and proliferation was determined by 3 H-thymidine incorporation. In separate experiments, regulatory T cells were added to induced pluripotent stem cell-derived pro-inflammatory macrophages and changes in interleukin-6/tumour necrosis-alpha transcripts and protein levels were measured. Freshly isolated regulatory T cells were expanded ex vivo in the presence of CD3/CD28 expander beads, interleukin-2 and rapamycin to promote their suppressive function. We found that the 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. CD25 mean fluorescence intensity in regulatory T-cell population was also reduced in Alzheimer dementia patients. Regulatory T cells did not suppress pro-inflammatory macrophages at baseline. Following ex vivo expansion, regulatory T-cell suppression of responder T-cell proliferation and pro-inflammatory macrophage activation increased in both patients and controls. Expanded regulatory T cells exerted their immunoregulatory function on pro-inflammatory macrophages through a contact-mediated mechanism. In conclusion, regulatory T-cell immunophenotype and function are compromised in Alzheimer's disease. Following ex vivo expansion, the immunomodulatory function of regulatory T cells is enhanced even at advanced stages of Alzheimer's disease. Restoration of regulatory T-cell function could be explored as a means to modulate the inflammatory status of Alzheimer's disease. Abstract : The suppressive function of regulatory T cells is compromised throughout the course of Alzheimer. Following ex vivo expansion, the immunoregulatory capacity of regulatory T cells was substantially enhanced through a cell contact-mediated mechanism. Restoration of regulatory T-cell dysfunction offers a unique therapeutic option to modulate neuroinflammation in Alzheimer's disease. Graphical Abstract: