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Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms

Nature Immunology volume 14, pages 380–388 (2013)Cite this article

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Abstract

The transcription factor Bcl-6 orchestrates germinal center (GC) reactions through its actions in B cells and T cells and regulates inflammatory signaling in macrophages. Here we found that genetic replacement with mutated Bcl6 encoding Bcl-6 that cannot bind corepressors to its BTB domain resulted in disruption of the formation of GCs and affinity maturation of immunoglobulins due to a defect in the proliferation and survival of B cells. In contrast, loss of function of the BTB domain had no effect on the differentiation and function of follicular helper T cells or that of other helper T cell subsets. Bcl6-null mice had a lethal inflammatory phenotype, whereas mice with a mutant BTB domain had normal healthy lives with no inflammation. The repression of inflammatory responses by Bcl-6 in macrophages was accordingly independent of the repressor function of the BTB domain. Bcl-6 thus mediates its actions through lineage-specific biochemical functions.

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Figure 1: Impaired GC formation in Bcl6BTBMUT mice.
Figure 2: Intact extrafollicular responses but impaired GC responses in Bcl6BTBMUT mice.
Figure 3: Bcl6BTBMUT mice show impaired GC responses in a B cell–autonomous manner.
Figure 4: The lateral groove of the Bcl-6 BTB domain is required for the proliferation and survival of GC B cells.
Figure 5: Normal GC responses in chimeras given Tcrb−/−Tcrd−/− and Bcl6BTBMUT bone marrow.
Figure 6: Normal TH2 and TH17 differentiation in Bcl6BTBMUT mice.
Figure 7: Bcl6BTBMUT mice do not develop TH2 inflammatory disease and have nearly normal inflammation-related gene expression in macrophages.

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Acknowledgements

We thank H. Ye (Albert Einstein College of Medicine) for Bcl6−/− mice; W. Pear (University of Pennsylvania) for the MIGR1 expression vector; and D. Wen and S. Rafii for assistance in generating Bcl6BTBMUT mice. Supported by the US National Cancer Institute (R01 104348 to A.M.), the Burroughs Wellcome Foundation and Chemotherapy Foundation (A.M.) and the March of Dimes (A.M.), and facilitated by the Sackler Center for Biomedical and Physical Sciences at Weill Cornell Medical College.

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  1. Division of Hematology and Oncology, Weill Cornell Medical College, New York, New York, USA

    Chuanxin Huang, Katerina Hatzi & Ari Melnick

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  1. Chuanxin Huang
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  2. Katerina Hatzi
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Contributions

C.H. designed and did most of the experiments; K.H. did and analyzed ChIP-seq experiments; and A.M. conceived of the project and wrote the manuscript.

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Correspondence to Ari Melnick.

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The authors declare no competing financial interests.

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Huang, C., Hatzi, K. & Melnick, A. Lineage-specific functions of Bcl-6 in immunity and inflammation are mediated by distinct biochemical mechanisms. Nat Immunol 14, 380–388 (2013). https://doi.org/10.1038/ni.2543

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