Aging impairs regulatory T cell (Treg) cells to affect late-onset (aged) multiple sclerosis (MS) - with the model of experimental autoimmune encephalomyelitis (EAE)

Abstract

Purpose: A master immunoregulator FoxP3-expressing CD4+Treg cells play an ameliorative role in the severity of MS/EAE disease. However, it remains to be determined why severe MS/EAE symptoms and pathology in the aged are co-existing with relatively enhanced thymic CD4+Treg generation and accumulated peripheral CD4+Treg cells. Methods: We immunized young and aged mice to induce EAE and investigated the disease courses and Treg cell associated mechanisms. Results: The EAE onset was delayed in aged mice, but the disease severity is increased relative to young mice. Using single-cell (sc)-RNA-Seq assay, we found that CNS-infiltrating CD4+Treg cells in aged EAE mice had increased pathogenic properties, showing co-expression of Infg and Il17a with Foxp3, and reduced suppressive effect, exhibiting increased clonal expansion of pathogenic CD4+ T cells. These indicate pathogenic changes in Treg quality in aged EAE mice. In addition, CNS-infiltrating CD8+ T cells also gained increased Infg and Il17a expressions in the aged EAE mice. Transient inhibition of aged peripheral FoxP3+ Treg cells mitigated the disease severity in the aged mice. The ameliorative effect was more significant when partially inhibiting FoxP3+ Treg cells with a drug P300i than completely depleting FoxP3+ Treg cells in FoxP3DTR transgenic mice. The mitigation is probably attributed to the correction of Treg cell distribution outside and inside the CNS. By inhibiting accumulated FoxP3+ Treg cells adhering to the brain's choroid plexus (outside the CNS), the IFN-γ-producing cells can be restored, thereby, the impediment of immune cell trafficking into the inflamed CNS is released in aged EAE mice. As a result, the proportion of myelin-specific CD4+Treg cells inside the CNS was increased for repairing neuroinflammatory damage. Conclusion: The underlying mechanism of severe MS symptoms in elderly patients is associated with the accumulation of Treg cells outside the CNS, which prevents the reparative antigen- specific Treg cells from entering the CNS during the disease.