The lower limit of regulatory CD4+ Foxp3++ TCRβ repertoire diversity required to control autoimmunity

Aixin Yu, Michael J. Dee, Dennis Adeegbe, Connor J. Dwyer, Norman H. Altman, Thomas Malek

Research output: Contribution to journalArticle

5 Citations (Scopus)

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 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.

Original languageEnglish (US)
Pages (from-to)3127-3135
Number of pages9
JournalJournal of Immunology
Volume198
Issue number8
DOIs
StatePublished - Apr 15 2017

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Autoimmunity
T-Lymphocytes
Self Tolerance
Autoantigens
Regulatory T-Lymphocytes
Population

ASJC Scopus subject areas

  • Immunology

Cite this

The lower limit of regulatory CD4+ Foxp3++ TCRβ repertoire diversity required to control autoimmunity. / Yu, Aixin; Dee, Michael J.; Adeegbe, Dennis; Dwyer, Connor J.; Altman, Norman H.; Malek, Thomas.

In: Journal of Immunology, Vol. 198, No. 8, 15.04.2017, p. 3127-3135.

Research output: Contribution to journalArticle

Yu, Aixin ; Dee, Michael J. ; Adeegbe, Dennis ; Dwyer, Connor J. ; Altman, Norman H. ; Malek, Thomas. / The lower limit of regulatory CD4+ Foxp3++ TCRβ repertoire diversity required to control autoimmunity. In: Journal of Immunology. 2017 ; Vol. 198, No. 8. pp. 3127-3135.
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