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The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells

Abstract

The transcription factor BATF controls the differentiation of interleukin 17 (IL-17)-producing helper T cells (TH17 cells) by regulating expression of the transcription factor RORγt itself and RORγt target genes such as Il17. Here we report the mechanism by which BATF controls in vivo class-switch recombination (CSR). In T cells, BATF directly controlled expression of the transcription factors Bcl-6 and c-Maf, both of which are needed for development of follicular helper T cells (TFH cells). Restoring TFH cell activity to Batf−/− T cells in vivo required coexpression of Bcl-6 and c-Maf. In B cells, BATF directly controlled the expression of both activation-induced cytidine deaminase (AID) and of germline transcripts of the intervening heavy-chain region and constant heavy-chain region (IH-CH). Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo.

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Figure 1: Defects in GC B cells and TFH cells in Batf−/− mice.
Figure 2: BATF is required for the expression of c-Maf and Bcl-6 by T cells activated in vitro.
Figure 3: BATF directly binds to conserved elements in Maf and Bcl6 in vivo.
Figure 4: BATF is required for optimal CD40 ligand expression.
Figure 5: Coexpression of Bcl-6 and c-Maf partially restores TFH cell activity in Batf−/− T cells.
Figure 6: Impaired class switching in Batf−/− B cells.
Figure 7: BATF directly regulates the expression of AID mRNA.
Figure 8: BATF is required for germline transcription.

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Acknowledgements

We thank T. Honjo (Kyoto University) for Aicda−/− mice; and D. Bhattacharya (Washington University) for retroviruses Bcl-6-GFP RV and CD40L-GFP RV. Supported by the Howard Hughes Medical Institute (K.M.M.).

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Contributions

W.I. designed experiments, did research, interpreted results and wrote the manuscript; M.K. helped with gene cloning, immunohistochemistry and microarray analysis; B.U.S. initiated analysis of in vivo antibody responses; T.Z., B.S., U.B. and F.W.A. helped with class-switch assays; J.T. and E.M.O. helped with ChIP assays; T.L.M. helped with EMSA; and K.M.M. directed the study and wrote the manuscript.

Corresponding author

Correspondence to Kenneth M Murphy.

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The authors declare no competing financial interests.

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Ise, W., Kohyama, M., Schraml, B. et al. The transcription factor BATF controls the global regulators of class-switch recombination in both B cells and T cells. Nat Immunol 12, 536–543 (2011). https://doi.org/10.1038/ni.2037

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