Accumulation of pTreg cells is detrimental in late‐onset (aged) mouse model of multiple sclerosis

Although typically associated with onset in young adults, multiple sclerosis (MS) also attacks the elderly, which is termed late‐onset MS. The disease can be recapitulated and studied in a mouse model, experimental autoimmune encephalomyelitis (EAE). The onset of induced EAE is delayed in aged mice, but disease severity is increased relative to young EAE mice. Given that CD4+FoxP3+ regulatory T (Treg) cells play an ameliorative role in MS/EAE severity, and the aged immune system accumulates peripheral Treg (pTreg) cells, failure of these cells to prevent or ameliorate EAE disease is enigmatic. When analyzing the distribution of Treg cells in EAE mice, the aged mice exhibited a higher proportion of polyclonal (pan‐) pTreg cells and a lower proportion of antigen‐specific pTreg cells in the periphery but lower proportions of both pan‐ and antigen‐specific Treg cells in the central nervous system (CNS). Furthermore, in the aged inflamed CNS, CNS‐Treg cells exhibited a higher plasticity, and T effector (CNS‐Teff) cells exhibited greater clonal expansion, disrupting the Treg/Teff balance. Transiently inhibiting FoxP3 or depleting pTreg cells partially corrected Treg distribution and restored the Treg/Teff balance in the aged inflamed CNS, thereby ameliorating the disease in the aged EAE mice. These results provide evidence and mechanism that accumulated aged pTreg cells play a detrimental role in neuronal inflammation of aged MS. Aged mice have accumulated peripheral Treg cells (pTregs) with severe EAE symptoms. Treg distribution is disrupted outside and inside the inflamed CNS, combined with increased CNS‐Treg plasticity. Transient inhibition of accumulated pTregs can redistribute Treg cells and mitigate the symptoms.