title: The Lower Limit of Regulatory CD4+Foxp3+TCRβ Repertoire Diversity Required To Control Autoimmunity.
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.
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Aixin
authors.identifier: 0000-0002-0557-8077
authors.initials: A
authors.lastname: Yu
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Dee
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Dennis
authors.identifier: 0000-0001-9233-3328
authors.initials: D
authors.lastname: Adeegbe
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Connor J
authors.initials: CJ
authors.lastname: Dwyer
authors.affiliation: Department of Pathology, Miller School of Medicine, University of Miami, Miami, FL 33136; and.
authors.forename: Norman H
authors.initials: NH
authors.lastname: Altman
authors.affiliation: Department of Microbiology and Immunology, Miller School of Medicine, University of Miami, Miami, FL 33136; tmalek@med.miami.edu.|Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, FL 33136.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Malek
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002469:Cell Separation; D005434:Flow Cytometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology*; D017634:Self Tolerance / Q000276:immunology*
chemical_list: D016693:Receptors, Antigen, T-Cell, alpha-beta