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

Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, Alt FW, Tang J, Oltz EM, Murphy TL, Murphy KM - Nat. Immunol. (2011)

Bottom Line: Restoring T(FH) 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 (I(H)-C(H)).Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

ABSTRACT
The transcription factor BATF controls the differentiation of interleukin 17 (IL-17)-producing helper T cells (T(H)17 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 (T(FH) cells). Restoring T(FH) 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 (I(H)-C(H)). Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo.

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Impaired class switching in Batf−/− B cells. (a) FACS analysis for IgA, IgM and B220 expression by lymphocytes from Peyer’s patches (PP) or Lamina propria (LPL) of Batf+/+ or Batf−/− mice was performed. Data are representative of two experiments. (b) Quantitative RT-PCR analysis of post-switched Iμ-CH transcripts (PST) in Batf+/+ or Batf−/− B-cells stimulated for 4 days as in Supplementary figure 10a, b. Expression is normalized to hprt expression and is presented relative to the expression in Batf+/+ B cells, set at 1. **P<0.0001 (unpaired student t-test). Data are from three independent experiments. (c) Digestion-circularization PCR assay of genomic DNA isolated from Batf+/+ or Batf−/− B-cells unstimulated (d0) or stimulated with LPS plus IL-4 for 4 days (d4) for measurement of Sμ-Sγ1 recombination. Data are representative of two experiments.
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Figure 6: Impaired class switching in Batf−/− B cells. (a) FACS analysis for IgA, IgM and B220 expression by lymphocytes from Peyer’s patches (PP) or Lamina propria (LPL) of Batf+/+ or Batf−/− mice was performed. Data are representative of two experiments. (b) Quantitative RT-PCR analysis of post-switched Iμ-CH transcripts (PST) in Batf+/+ or Batf−/− B-cells stimulated for 4 days as in Supplementary figure 10a, b. Expression is normalized to hprt expression and is presented relative to the expression in Batf+/+ B cells, set at 1. **P<0.0001 (unpaired student t-test). Data are from three independent experiments. (c) Digestion-circularization PCR assay of genomic DNA isolated from Batf+/+ or Batf−/− B-cells unstimulated (d0) or stimulated with LPS plus IL-4 for 4 days (d4) for measurement of Sμ-Sγ1 recombination. Data are representative of two experiments.

Mentions: Because the defect in switched antibody responses in Batf−/− B cells was B cell-intrinsic (Supplementary Fig. 4c), we examined the secretion and surface expression of antibody using an in vitro class switching system (Supplementary Fig. 10a, b). We found dramatic reductions for each of the switched isotypes, IgG1, IgG2a, IgG2b, IgG3, and IgA. This defect occurs in vivo, shown by absent surface IgA expression of B cells from Peyer’s patches and lamina propria (Fig. 6a), but is not caused by altered B cell proliferation, a requirement for class switching20–22 or plasmacyte differentiation, since Batf−/− B cells proliferate normally and express the plasma cell marker CD138 (syndecan)23,24 (Supplementary Fig. 10c, 11).


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

Ise W, Kohyama M, Schraml BU, Zhang T, Schwer B, Basu U, Alt FW, Tang J, Oltz EM, Murphy TL, Murphy KM - Nat. Immunol. (2011)

Impaired class switching in Batf−/− B cells. (a) FACS analysis for IgA, IgM and B220 expression by lymphocytes from Peyer’s patches (PP) or Lamina propria (LPL) of Batf+/+ or Batf−/− mice was performed. Data are representative of two experiments. (b) Quantitative RT-PCR analysis of post-switched Iμ-CH transcripts (PST) in Batf+/+ or Batf−/− B-cells stimulated for 4 days as in Supplementary figure 10a, b. Expression is normalized to hprt expression and is presented relative to the expression in Batf+/+ B cells, set at 1. **P<0.0001 (unpaired student t-test). Data are from three independent experiments. (c) Digestion-circularization PCR assay of genomic DNA isolated from Batf+/+ or Batf−/− B-cells unstimulated (d0) or stimulated with LPS plus IL-4 for 4 days (d4) for measurement of Sμ-Sγ1 recombination. Data are representative of two experiments.
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Figure 6: Impaired class switching in Batf−/− B cells. (a) FACS analysis for IgA, IgM and B220 expression by lymphocytes from Peyer’s patches (PP) or Lamina propria (LPL) of Batf+/+ or Batf−/− mice was performed. Data are representative of two experiments. (b) Quantitative RT-PCR analysis of post-switched Iμ-CH transcripts (PST) in Batf+/+ or Batf−/− B-cells stimulated for 4 days as in Supplementary figure 10a, b. Expression is normalized to hprt expression and is presented relative to the expression in Batf+/+ B cells, set at 1. **P<0.0001 (unpaired student t-test). Data are from three independent experiments. (c) Digestion-circularization PCR assay of genomic DNA isolated from Batf+/+ or Batf−/− B-cells unstimulated (d0) or stimulated with LPS plus IL-4 for 4 days (d4) for measurement of Sμ-Sγ1 recombination. Data are representative of two experiments.
Mentions: Because the defect in switched antibody responses in Batf−/− B cells was B cell-intrinsic (Supplementary Fig. 4c), we examined the secretion and surface expression of antibody using an in vitro class switching system (Supplementary Fig. 10a, b). We found dramatic reductions for each of the switched isotypes, IgG1, IgG2a, IgG2b, IgG3, and IgA. This defect occurs in vivo, shown by absent surface IgA expression of B cells from Peyer’s patches and lamina propria (Fig. 6a), but is not caused by altered B cell proliferation, a requirement for class switching20–22 or plasmacyte differentiation, since Batf−/− B cells proliferate normally and express the plasma cell marker CD138 (syndecan)23,24 (Supplementary Fig. 10c, 11).

Bottom Line: Restoring T(FH) 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 (I(H)-C(H)).Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA.

ABSTRACT
The transcription factor BATF controls the differentiation of interleukin 17 (IL-17)-producing helper T cells (T(H)17 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 (T(FH) cells). Restoring T(FH) 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 (I(H)-C(H)). Thus, BATF functions at multiple hierarchical levels in two cell types to globally regulate switched antibody responses in vivo.

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