Maintenance of immune tolerance during aging requires competitive expansion of memory phenotype regulatory T cells

Memory phenotype (MP) CD4+ T cells accumulate with age; however, the immunological significance of this population shift and the mechanisms that preserve MP T-cell fitness remain poorly understood. Here, we show that age-associated accumulation of MP T cells is regulated by intra-clonal competition and that competitive expansion of MP regulatory T (Treg) cells is required for maintenance of immune tolerance during aging. Using MLL1 deficiency as a model, we found that Mll1-deficient T cells failed to undergo normal age-associated accumulation and were progressively outcompeted by wild-type (WT) cells despite retaining the ability to proliferate and generate MP populations in the absence of competitors. Mechanistically, MLL1 preserved competitive fitness by maintaining transcription of TCR variable region genes and sustaining T-cell receptor expression during proliferation. Loss of competitive fitness impaired MP Treg-cell expansion and disrupted immune homeostasis. Remarkably, a small population of WT Treg cells restored tolerance through extensive expansion of MP Treg cells. These findings identify competitive expansion of MP Treg cells as a critical mechanism for maintaining immune tolerance during aging.