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

Immunology. 2015 May;145(1):11-23. doi: 10.1111/imm.12393.


Foxp3(+) regulatory T (Treg) cells are essential to maintain immune homeostasis, yet controversy exists about the stability of this cell population. Bcl6-deficient (Bcl6(-/-) ) 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(-/-) mice, increased numbers of Foxp3-negative 'exTreg' cells were found, particularly in the CD25(+) population. ExTreg cells from Bcl6(-/-) 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(-/-) 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(Foxp3-/-) ) mice were analysed. Bcl6(Foxp3-/-) mice do not develop inflammatory disease, indicating a requirement for non-Treg cells for inflammation in Bcl6(-/-) mice, and have normal numbers of exTreg cells. We induced Th2-type allergic airway inflammation in Bcl6(Foxp3-/-) 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(+) Treg cells. Bcl6(Foxp3-/-) 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.

Keywords: Bcl6; FoxP3; T helper type 2 differentiation; ex-regulatory T cells; regulatory T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Asthma / genetics
  • Asthma / immunology*
  • Asthma / pathology
  • Cytokines / genetics
  • Cytokines / immunology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / immunology*
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / immunology
  • GATA3 Transcription Factor / genetics
  • GATA3 Transcription Factor / immunology
  • Gene Expression Regulation / genetics
  • Gene Expression Regulation / immunology*
  • Inflammation / genetics
  • Inflammation / immunology
  • Inflammation / pathology
  • Interleukin-2 Receptor alpha Subunit / genetics
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Mice
  • Mice, Knockout
  • Proto-Oncogene Proteins c-bcl-6
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / pathology
  • Th2 Cells / immunology*
  • Th2 Cells / pathology


  • Bcl6 protein, mouse
  • Cytokines
  • DNA-Binding Proteins
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • GATA3 Transcription Factor
  • Gata3 protein, mouse
  • Il2ra protein, mouse
  • Interleukin-2 Receptor alpha Subunit
  • Proto-Oncogene Proteins c-bcl-6