Accumulation of Treg cells is detrimental in late-onset (aged) mouse model of multiple sclerosis

Abstract

Although typically associated with onset in young adults, multiple sclerosis (MS) also attacks aged people, which is termed late-onset MS. The disease can be recapitulated and studied in the aged mouse model of experimental autoimmune encephalomyelitis (EAE). The onset of induced EAE is delayed in aged mice, but the disease severity is increased relative to standard EAE in young mice. Given that CD4+FoxP3+ regulatory T (Treg) cells play an ameliorative role in MS/EAE severity and the aged immune system accumulates Treg 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) Treg cells and a lower proportion of antigen-specific-Treg cells in their periphery, but lower proportions of pan- and antigen-specific-Treg cells in the central nervous system (CNS). Furthermore, in the aged CNS, Treg cells exhibited a higher plasticity and T effector (Teff) cells exhibited a greater clonal expansion, which disrupted the Treg/Teff balance. Transiently inhibiting FoxP3 expression in peripheral Treg cells partially ameliorated the disease and corrected Treg distribution in the aged mice. These results provide evidence that accumulated aged Treg cells play a detrimental role in neuronal inflammation of aged MS. HighlightsO_ST_ABSQuestionC_ST_ABSCD4+ regulatory T (Treg) cells typically play an ameliorative role in multiple sclerosis (MS) onset and severity. However, why aged immune system has accumulated peripheral Treg cells, but the elderly has more severe MS symptoms? FindingsAged Treg cells cannot easily distribute to the CNS of aged EAE mice, and those aged Treg cells that did enter the CNS exhibited increased plastic features. However, transient inhibition of peripherally accumulated Treg cells corrected Treg distribution and partially ameliorated the disease in the aged mice. Conclusion and mechanistic insightsAccumulated aged Treg cells within an "inflammaging" condition do not play an ameliorative role but are potentially detrimental for inflamed CNS repair processes in aged EAE mice due to impeding the trafficking of immune cells into the inflamed CNS. O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY