The Lower Limit of Regulatory CD4+ Foxp3+ TCRβ Repertoire Diversity Required To Control Autoimmunity
Year: 2017
Type: article
Abstract: 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 TCRβ repertoire was reshaped and further narrowed. In contrast, secondary IL-2Rβ recipients showed fewer symptoms of autoimmunity when they received donor Tregs that were premixed from several primary recipients to increase their TCRβ repertoire diversity. About 8–11% of the Treg TCRβ 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 TCRβ 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.
Source: The Journal of Immunology
Institution: University of Miami
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2592570385