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Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile

Nature Immunology volume 13, pages 405–411 (2012)Cite this article

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Abstract

The transcription factors T-bet and Bcl-6 are required for the establishment of a T helper type 1 cell (TH1 cell) and follicular helper T cell (TFH cell) gene-expression profile, respectively. Here we found that high concentrations of interleukin 2 (IL-2) inhibited Bcl-6 expression in polarized TH1 cells. Mechanistically, the low concentrations of Bcl-6 normally found in effector TH1 cells did not repress its target genes because a T-bet–Bcl-6 complex masked the Bcl-6 DNA-binding domain. TH1 cells increased their Bcl-6/T-bet ratio in response to limiting IL-2 conditions, which allowed excess Bcl-6 to repress its direct target Prdm1 (which encodes the transcriptional repressor Blimp-1). The Bcl-6-dependent repression of Blimp-1 effectively induced a partial TFH profile because Blimp-1 directly repressed a subset of TFH signature genes, including Cxcr5. Thus, IL-2-signaling regulates the Bcl-6–Blimp-1 axis in TH1 cells to maintain flexibility with a TFH cell–like gene profile.

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Figure 1: A T-bet–Bcl-6 complex inhibits Bcl-6-dependent repression.
Figure 2: IL-2-signaling inhibits Bcl-6 expression in TH1 cells.
Figure 3: STAT and Foxo transcription factors regulate Bcl6.
Figure 4: IL-2 regulates the expression of Prdm1 and TFH cell–associated genes in TH1 cells.
Figure 5: TH1 cells maintain IL-2-sensitive Bcl-6 and TFH gene regulation.
Figure 6: Blimp-1 directly represses TFH genes in effector TH1 cells.

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Acknowledgements

We thank the National Cancer Institute preclinical repository for IL-2 and anti-IL-4; members of the Weinmann laboratory for discussions; and M. Wijaranakula for technical assistance. Supported by the National Institute of Allergy and Infectious Diseases (AI061061 and AI07272 to A.S.W.) and the American Cancer Society (RSG-09-045-01-DDC to A.S.W.).

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  1. Department of Immunology, University of Washington, Seattle, Washington, USA

    Kenneth J Oestreich, Sarah E Mohn & Amy S Weinmann

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  1. Kenneth J Oestreich
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Contributions

K.J.O. and A.S.W. designed and did experiments, analyzed data and wrote the manuscript; and S.E.M contributed to the experiments in Figures 1c and 2b,e, and Supplementary Figure 4a,b.

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Correspondence to Amy S Weinmann.

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Oestreich, K., Mohn, S. & Weinmann, A. Molecular mechanisms that control the expression and activity of Bcl-6 in TH1 cells to regulate flexibility with a TFH-like gene profile. Nat Immunol 13, 405–411 (2012). https://doi.org/10.1038/ni.2242

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