Ageing impairs the regenerative capacity of regulatory T cells in central nervous system remyelination

Abstract

Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis but its efficiency declines with age. Regulatory T cells (Treg) recently emerged as critical players in tissue regeneration, including remyelination. However, the effect of ageing on Treg-mediated regenerative processes is poorly understood. Here, we show that expansion of aged Treg does not rescue age-associated remyelination impairment due to an intrinsically diminished capacity of aged Treg to promote oligodendrocyte differentiation and myelination. This decline in regenerative Treg functions can be rescued by a young environment. We identified Melanoma Cell Adhesion Molecule 1 (MCAM1) and Integrin alpha 2 (ITGA2) as novel candidates of Treg-mediated oligodendrocyte differentiation that decrease with age. Our findings demonstrate that ageing limits the neuroregenerative capacity of Treg, likely limiting their remyelinating therapeutic potential in aged patients and describe two novel mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.

Differential roles of regulatory T cells in acute respiratory infections

“…Age-related alterations in DNA methylation patterning are a core hallmark of aging (108), and in our study, genome-wide DNA methylation profiling revealed that age-related epigenetic alterations explained the loss of reparative transcriptional programs following influenza infection. Beyond the lung, a growing body of literature suggests that age-related Treg dysfunction affects other tissues and organs, including adipose tissue, skeletal muscle, and the nervous system (29,111,112). In addition to age, sex and gender are important biological and demographic variables, respectively, that are associated with differential risks from severe pneumonia, including due to SARS-CoV-2, with male sex and gender consistently demonstrating increased susceptibility (113)(114)(115).…”