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.
- Ex-regulatory T cells
- Regulatory T cells
- T helper type 2 differentiation
ASJC Scopus subject areas
- Immunology and Allergy