The transcriptional repressor Bcl6 controls the stability of regulatory T cells by intrinsic and extrinsic pathways

Deepali V. Sawant, Hao Wu, Weiguo Yao, Sarita Sehra, Mark H. Kaplan, Alexander L. Dent

Research output: Contribution to journalArticle

14 Scopus citations

Abstract

Foxp3<sup>+</sup> regulatory T (Treg) cells are essential to maintain immune homeostasis, yet controversy exists about the stability of this cell population. Bcl6-deficient (Bcl6<sup>-/-</sup>) mice develop severe and spontaneous T helper type 2 (Th2) inflammation and Bcl6-deficient Treg cells are ineffective at controlling Th2 responses. We used a lineage tracing approach to analyse the fate of Treg cells in these mice. In the periphery of Bcl6<sup>-/-</sup> mice, increased numbers of Foxp3-negative 'exTreg' cells were found, particularly in the CD25<sup>+</sup> population. ExTreg cells from Bcl6<sup>-/-</sup> mice expressed increased interleukin-17 (IL-17) and extremely elevated levels of Th2 cytokines compared with wild-type exTreg cells. Although Treg cells normally express only low levels of cytokines, Treg cells from Bcl6<sup>-/-</sup> mice secreted higher levels of IL-4, IL-5, IL-13 and IL-17 than wild-type conventional T cells. Next, Treg-specific conditional Bcl6-deficient (Bcl6<sup>Foxp3-/-</sup>) mice were analysed. Bcl6<sup>Foxp3-/-</sup> mice do not develop inflammatory disease, indicating a requirement for non-Treg cells for inflammation in Bcl6<sup>-/-</sup> mice, and have normal numbers of exTreg cells. We induced Th2-type allergic airway inflammation in Bcl6<sup>Foxp3-/-</sup> mice, and found that while exTreg cytokine expression was normal, Bcl6-deficient Treg cells expressed higher levels of the Th2-specific regulator Gata3 than Bcl6<sup>+</sup> Treg cells. Bcl6<sup>Foxp3-/-</sup> mice had increased numbers of Th2 cells after induction of airway inflammation and increased T cells in the bronchoalveolar lavage fluid. These data show both Treg-intrinsic and Treg-extrinsic roles for Bcl6 in controlling Treg cell stability and Th2 inflammation, and support the idea that Bcl6 expression in Treg cells is critical for controlling Th2 responses.

Original languageEnglish (US)
Pages (from-to)11-23
Number of pages13
JournalImmunology
Volume145
Issue number1
DOIs
StatePublished - May 1 2015

Keywords

  • Bcl6
  • Ex-regulatory T cells
  • FoxP3
  • Regulatory T cells
  • T helper type 2 differentiation

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

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