Aging impairs regulatory T cells to affect the mouse model of late-onset multiple sclerosis

Although multiple sclerosis (MS) primarily onsets in young adults, it can also develop in the elderly, which is termed late-onset (aged) MS. CD4+ Foxp3 + regulatory T (Treg) cells play an ameliorative role in severity of MS or its animal model experimental autoimmune encephalomyelitis (EAE), and the aged immune system accumulates peripheral Treg (pTreg) cells. However, late-onset MS in the aged patients presents a more progressive disease course. We investigated why the accumulated pTreg cells fail to ameliorate the MS severity in the aged individuals by using an aged EAE mouse model to recapitulate late-onset MS in patients. We observed that the onset of EAE is delayed in aged mice, but disease severity is increased compared to young EAE mice. We found that the distribution of Treg cells in aged EAE mice exhibited an increased proportion of polyclonal (pan-) pTreg cells and a decreased proportion of antigen specific-pTreg cells in the periphery, but decreased proportions of both pan- and antigen specificTreg cells in the central nervous system (CNS). Transiently inhibiting Foxp3 or depleting pTreg cells partially corrected Treg distribution and restored the balance of effector T cells (Teff) and Treg cells in the aged inflamed CNS, thereby ameliorating the disease in the aged EAE mice. Furthermore, in the aged inflamed CNS, CNS-Treg cells exhibited a high plasticity and T effector (CNS-Teff) cells presented a great clonal expansion, disrupting the Treg/Teff balance. These results provide evidence and mechanism that accumulated aged pTreg cells play a detrimental role in neuronal inflammation of aged MS.