The TCR repertoire of regulatory T cells (Tregs) is highly diverse. The relevance of this diversity to maintain self-tolerance remains unknown. We established a model where the TCR repertoire of normal polyclonal Tregs was limited by serial transfers into IL-2Rβ-/- mice, which lack functional Tregs. After a primary transfer, the donor Treg TCR repertoire was substantially narrowed, yet the recipients remained autoimmune-free. Importantly, upon purification and transfer of donor-derived Tregs from an individual primary recipient into neonatal IL-2Rβ-/- mice, the secondary recipients developed autoimmunity. In this study, the Treg TCRb repertoire was reshaped and further narrowed. In contrast, secondary IL-2Rb recipients showed fewer symptoms of autoimmunity when they received donor Tregs that were premixed from several primary recipients to increase their TCRb repertoire diversity. About 8-11% of the Treg TCRb repertoire was estimated to be the minimum required to establish and maintain tolerance in primary IL-2Rβ-/- recipients. Collectively, these data quantify where limitations imposed on the Treg TCRb repertoire results in a population of Tregs that cannot fully suppress polyclonal autoreactive T cells. Our data favor a model where the high diversity of the Treg TCR provides a mechanism for Tregs to actively adapt and effectively suppress autoreactive T cells, which are not fixed, but are evolving as they encounter self-antigens.
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