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The transcriptional programme of antibody class switching involves the repressor Bach2

Abstract

Activated B cells differentiate to plasma cells to secrete IgM or, after undergoing class switch recombination (CSR), to secrete other classes of immunoglobulins1,2,3,4. Diversification of antibody function by CSR is important for humoral immunity. However, it remains unclear how the decision for the bifurcation is made. Bach2 is a B-cell-specific transcription repressor interacting with the small Maf proteins whose expression is high only before the plasma cell stage5,6,7. Here we show that Bach2 is critical for CSR and somatic hypermutation (SHM)2,4,8 of immunoglobulin genes. Genetic ablation of Bach2 in mice revealed that Bach2 was required for both T-cell-independent and T-cell-dependent IgG responses and SHM. When stimulated in vitro, Bach2-deficient B cells produced IgM, as did wild-type cells, and abundantly expressed Blimp-1 (refs 9, 10) and XBP-1 (ref. 11), critical regulators of the plasmacytic differentiation12, indicating that Bach2 was not required for the plasmacytic differentiation itself. However, they failed to undergo efficient CSR. These findings define Bach2 as a key regulator of antibody response and provide an insight into the orchestration of CSR and SHM during plasma cell differentiation.

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Figure 1: B-cell development in Bach2-deficient mice.
Figure 2: Impaired antibody production and SHM in Bach2-deficient mice.
Figure 3: Impaired CSR in the Bach2-deficient B cells.
Figure 4: Characterization of genetic circuitry involving Bach2.

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Acknowledgements

We thank M. Kobayashi, D. Engel, M. Muramatsu and T. Honjo for discussion and comments on the manuscript, M. Busslinger for information on RT–PCR analysis, N. Kaneko for the preparation of tissue sections, and M. Kanno for the use of FACS machinery. This work was supported by Grants-in-aid from the Ministry of Education, Culture, Sport, Science and Technology of Japan and Hiroshima University 21st century COE programme. A.M. was initially supported by the Research Fellowships for Young Scientists from the Japanese Society for Promotion of Science.

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Correspondence to Kazuhiko Igarashi.

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Supplementary information

Supplementary Figure 1

a, Targeting strategy of mouse bach2 gene. b, Southern blot analysis of DNA prepared from the control and targeted embryonic stem (ES) cell clones. c, Western blot analysis of bone marrow B cell extracts of each genotype with anti-Bach2.

Supplementary Figure 2a

Nucleotide sequences of Vh186.2 mRNAs from MLN of bach2+/+ mice 28 days after primary immunization with NP-CGG.

Supplementary Figure 2b

Nucleotide sequences of Vh186.2 mRNAs from MLN of bach2-/- mice 28 days after primary immunization with NP-CGG.

Supplementary Figure 2c

Nucleotide sequence of Vh186.2, DH and JH joints amplified from the mRNA of MLN cells of the NP-CGG immunized bach2+/+ and bach2-/- mice.

Supplementary Figure 3

Purified spleen B cells from wild-type and bach2-/- mice were cultured with LPS for 48 hrs and BrdU for last 6 hrs. BrdU incorporations were measured.

Supplementary Figure Legends

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Muto, A., Tashiro, S., Nakajima, O. et al. The transcriptional programme of antibody class switching involves the repressor Bach2. Nature 429, 566–571 (2004). https://doi.org/10.1038/nature02596

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