Ageing impairs the regenerative capacity of regulatory T cells in mouse central nervous system remyelination.
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Myelin regeneration (remyelination) is essential to prevent neurodegeneration in demyelinating diseases such as Multiple Sclerosis, however, 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 in male and female mice. 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 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 mechanisms implicated in Treg-driven remyelination that may be targetable to overcome this limitation.
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Acknowledgements: We acknowledge extensive technical support from Carmel McVicar, Maria P Athanasios, Michelle Naughton and the staff of the animal facility. We thank A. Rudensky (Memorial Sloan Kettering Cancer Centre) for providing Foxp3-DTR mice. We thank the laboratory of Anna Williams (University of Edinburgh) for the Fiji plug-in to analyse myelination index in brain slice cultures. This work was supported by the Wellcome Trust (110138/Z/15/Z to D.C.F.), Biotechnology and Biological Sciences Research Council (BB/J01026X/1 and BB/N003721/1, to D.C.F.), ECTRIMS postdoctoral fellowship (to A.G.F.), Wellcome ISSF fellowship (to A.G.F.), Miguel Servet Fellowship from the Spanish Institute of Health Carlos III (CP21/00032 to A.G.F.), Spanish State Research Agency Plan Generación de Conocimiento 2021 grant (PID2021-124465OA-I00 to A.G.F.), The Leverhulme Trust (ECF-2014-390, to Y.D.), a postdoctoral fellowship contract from the Generalitat Valenciana APOSTD21 (to F.J.R.) and postgraduate studentship support from the Dept. for the Economy (Northern Ireland).
Funder: Spanish State Research Agency Plan Generación de Conocimiento 2021 grant (PID2021-124465OA-I00)
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2041-1723
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RCUK | Biotechnology and Biological Sciences Research Council (BBSRC) (BB/J01026X/1, BB/N003721/1)
European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS) (Postdoctoral Fellowship)
Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III) (CP21/00032)