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Regulated selection of germinal-center cells into the memory B cell compartment

Abstract

Despite the importance of memory B cells in protection from reinfection, how such memory cells are selected and generated during germinal-center (GC) reactions remains unclear. We found here that light-zone (LZ) GC B cells with B cell antigen receptors (BCRs) of lower affinity were prone to enter the memory B cell pool. Mechanistically, cells in this memory-prone fraction had higher expression of the transcriptional repressor Bach2 than that of their counterparts with BCRs of higher affinity. Haploinsufficiency of Bach2 resulted in reduced generation of memory B cells, independently of suppression of the gene encoding the transcription factor Blimp-1. Bach2 expression in GC cells was inversely correlated with the strength of help provided by T cells. Thus, we propose an instructive model in which weak help from T cells maintains relatively high expression of Bach2, which predisposes GC cells to enter the memory pool.

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Figure 1: Low-affinity GC cells are 'preferentially' selected into the memory B cell compartments.
Figure 2: Transcriptome analysis of high- and low-affinity LZ GC B cells.
Figure 3: Restoration of the impaired population expansion and GC differentiation of Bach2-deficient B cells by ablation of Blimp-1.
Figure 4: Bach2 is required for the generation of memory B cells in a Blimp-1-independent manner.
Figure 5: Generation of influenza-virus-specific class-switched memory B cells requires Bach2.
Figure 6: Regulation of Bach2 expression.
Figure 7: The development of memory B cells is diminished by Bach2 haploinsufficiency.

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Acknowledgements

We thank D.L. Court (National Cancer Institute) for plasmid pSIM18 for the generation of BAC-transgenic mice; J.G. Cyster (UC San Francisco) for Hy10 mice; E. Hobeika and M. Reth (Max Planck Institute of Immunobiology and Epigenetics) for Mb1-Cre mice; M. Nussenzweig (The Rockefeller University) for B1-8hi mice, anti-DEC205–OVA and anti-DEC205–CS; G.D. Victora (Whitehead Institute for Biomedical Research) for gene sets for the gene-set-enrichment analysis; O. Ohara, T. Watanabe and Y. Mochizuki for transcriptome analysis; W. Ise for discussions; M. Tochigi, C. Kawai, A. Arakawa and H. Masuda for technical assistance; P. Burrows for critical reading; and R. Brink for communicating unpublished results. Supported by the Ministry of Education, Culture, Sports, Science, and Technology of Japan (A212290070, A262213060 to T.K.; and T268603430 to R.S.) and Japan Science and Technology (CREST) (J098501018 JST to T.K.).

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R.S., T.I., K.K. and T.K. designed the experiments; R.S., T.I. and K.K. performed most of the experiments; S.M., T.O. and K.K. generated S1pr2-ERT2cre mice; Y.A. and Y.T. performed the influenza infection experiment; M.N. provided technical advice and materials for the generation of S1pr2-ERT2cre mice; Y.T., H.F. and T.O. provided experimental advice and study design; K.K. and H.F. generated B1-8ge mice; S.M. and T.O. generated the Bcl6-expressing retroviral vector; and R.S. and T.K. wrote the paper with the assistance of all other authors.

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Correspondence to Tomohiro Kurosaki.

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Integrated supplementary information

Supplementary Figure 1 Expression of S1pr2 and construction of S1pr2-ERT2cre mice.

(a) qRT-PCR analysis of S1pr2 mRNA in naïve B cells (B220+CD138CD38+IgD+), activated B cells (NP+B220+CD138CD38+) at day 3, IgG1+ LZ GC (NP+B220+CD138CD38GL7+IgG1+CXCR4loCD86hi), DZ GC (NP+B220+CD138CD38GL7+IgG1+CXCR4hiCD86lo) B cells and plasmablasts/plasma cells (NP+B220loCD138+) at day 10, and IgG1+ memory B cells (NP+B220+CD38+IgG1+) at day 28. Samples are prepared from splenocytes of NP-CGG immunized wild-type mice. (b) Schematic representation of the structure of the S1pr2-ERT2cre BAC transgenic mice. (c) Flow cytometry of tdTomato+ cells among splenic NP-specific plasmablasts/plasma cells (NP+B220loIgG1+CD138+), IgG1+ memory B cells (NP+B220+IgG1+CD38+) and GC B cells (NP+B220+IgG1+CD38GL7+) in NP-CGG immunized S1pr2-ERT2cre-tdTomato mice at day 10. The mice were treated with tamoxifen for 12 h before analysis (left). Bar graph showing the percentage of tdTomato+ cells in each population (right). (d) Schematic illustration of the experimental protocol for Fig. 1b. (e) Absolute numbers of tdTomato+IgG1+ memory (left) and GC B cells (right) for determining ratio (Memory/GC) in Fig. 1b. (f) Frequency of W33L+ or W33G99 B cells (as in Fig. 1c) among NP-specific tdTomato+IgG1+ LZ GC (CD38CD86hiCXCR4lo) B cells and memory (CD38+) B cells from S1pr2-ERT2cre-tdTomato mice treated with tamoxifen for 2 d beginning at day 18 after NP-CGG-immunization (upper), and quantification of mutations in sequence encoding VH186.2 in those cells (lower). Each symbol (f) represents an individual cell; small horizontal lines indicate the mean. ***p < 0.001 (unpaired Student’s t-test). Data are pooled from two independent experiments (a; mean and s.d. n=3 samples), representative of two independent experiments (c; mean and s.d. n=3 mice), pooled from three independent experiments (e; mean of n=4 mice (day 8 and 32), n=5 mice (day 12 and 22)) and representative of three independent experiments (f; mean).

Supplementary Figure 2 Validation of a probe for the detection of NP-specific B cells.

(a, b) Flow cytometry of the whole splenocytes (a) and B220+ splenocytes (b) in wild-type mice at day 10 after immunization with CGG (upper panels) or NP-CGG (lower panels). Each data is representative of two independent experiments.

Supplementary Figure 3 Upregulation of Blimp-1 expression in Bach2-deficient activated B cells.

(a) Schematic illustration of the experimental protocol for Fig. 3. (b) qRT-PCR analysis of Bach2 and Prdm1 mRNA among activated Bach2+/+ ERT2cre B1-8hi or Bach2f/f ERT2cre B1-8hi B cells in spleen of NP-CGG immunized CD45.2+ wild-type recipient mice transferred with Bach2+/+ ERT2cre B1-8hi or Bach2f/f ERT2cre B1-8hi naive B cells with tamoxifen for 4 days before immunization. Samples were sorted at day 2 after immunization. (c) qRT-PCR analysis of Bach2 and Prdm1 mRNA in Bach2+/+Prdm1+/+ ERT2cre B1-8hi,Bach2+/+Prdm1f/f ERT2cre B1-8hi or Bach2f/fPrdm1f/f ERT2cre B1-8hi NP-specific donor GC B cells (NP+B220+CD38GL7+) to check the deletion efficiency for Fig. 3c and 3e. (d) Intracellular flow cytometry of Bcl-6 expression in NP-specific donor GC B cells (NP+B220+CD38GL7+) from experiments in Fig. 3e. The gray histogram represents the naïve B cells. **p < 0.01 and ***p < 0.001 (unpaired Student’s t-test). Data are representative of two independent experiments (b, c; mean and s.d. n=3 mice) and three independent experiments (d).

Supplementary Figure 4 Effect of Bach2 deletion on the development of memory B cells and regulation of Bach2 expression.

(a) Schematic illustration of the experimental protocol for Fig. 4. (b) qRT-PCR analysis of Bach2 and Prdm1 mRNA in Bach2+/+Prdm1+/+ Mb1-cre, Bach2+/+Prdm1f/f Mb1-cre, or Bach2f/fPrdm1f/f Mb1-cre naive B cells to check the deletion efficiency for Fig. 5. (c) The graphs indicate the absolute numbers of NP-specific IgG1+ memory B cells (NP+B220+IgG1+CD38+) and GC B cells (NP+B220+IgG1+CD38) in the NP-CGG immunized Bach2+/+Prdm1+/+ Mb1-cre, Bach2+/+Prdm1f/f Mb1-cre or Bach2f/fPrdm1f/f Mb1-cre mice at day 28. (d, e, f) Schematic illustration of the experimental protocol for Fig. 5 (d), Fig. 6c (e), Fig. 6d (f), respectively. *p < 0.05 and **p < 0.01 (unpaired Student’s t-test). Each symbol (c) represents an individual mouse. Data are from one experiment (b; mean n=2 mice) and representative of three independent experiments (c; mean)

Supplementary Figure 5 Transcriptome analysis of LZ GC B cells with low or high Bach2 expression.

(a) Flow cytometry of Bach2-reporter expression in NP-specific IgG1+ LZ GC B cells (NP+B220+IgG1+CD138CD38CXCR4loCD86hi) from NP-CGG immunized Bach2-reporter mice at day 10 (upper left). VH186.2 sequences analysis of Bach2-reporter expression low- and high-NP-specific IgG1+ LZ GC B cells (lower left and right). The pie charts and the numbers of mutations are described as in Fig. 1c. Gray histograms represent the non-Bach2-reporter wild-type control. (b) Venn diagrams illustrating the overlap between the high-affinity population (magenta) and Bach2-reporter low-population (green) (left) or between the low-affinity population (orange) and Bach2-reporter high-population (blue) (right). The lists of up-regulated genes for each population were from the differentially expressed genes (FDR <0.05) between the high- and low-affinity populations or between the Bach2-reporter low- and high-populations. In the case of Fig. 2b analysis, we selected up the genes whose difference was more than 2-fold. (c) Heatmaps between Bach2-reporter low- and high-populations are shown as normalized expression (log2) of selected genes which were listed in Fig. 2c. (d) qRT-PCR analysis of the indicated genes in Bach2-reporter low- and high-NP-specific IgG1+ LZ GC B cells.*p < 0.05, **p < 0.01 and ***p < 0.001 (unpaired Student’s t-test). Data are representative of three independent experiments (a; mean), are from one experiment with three biological replicates (b and c; mean in b) and are pooled from three independent experiments (d; mean and s.d. n=3 samples (each prepared from 2 to 3 mice)).

Supplementary Figure 6 GC B cells and plasmablasts-PCs are the main proliferating cells at day 10 after immunization.

(a) Schematic illustration of the experimental protocol for Fig. 7. (b) qRT-PCR analysis of Bach2 mRNA to check the deletion efficiency of Bach2 haploid insufficient B cells. NP-specific IgG1+ donor GC B cells (NP+B220+IgG1+CD38GL7+) were obtained from experiments in Fig. 7a. (c) Flow cytometry of EdU incorporated proliferating cells among splenic NP-specific IgG1+ plasmablasts/plasma cells (CD45.1+NP+B220loIgG1+CD138+), memory B cells (CD45.1+NP+B220+IgG1+CD138CD38+) and GC B cells (CD45.1+NP+B220+IgG1+CD138CD38GL7+) in the NP-CGG immunized CD45.2+ wild-type recipient mice given transferred with CD45.1+ B1-8ge naïve B cells. At day10 post-immunization, the mice were treated with 1 mg EdU i.p. for 30 min before analysis (left). Bar graph showing the percentage of EdU+ cells in each population (right). Data are pooled from two independent experiments (b; mean and s.d. n=3 mice) and representative of two independent experiments (c; mean and s.d. n=3 mice).

Supplementary Figure 7 Fate ‘decision’ is dependent on the strength of T cell help.

(a) Schematic illustration of the experimental protocol. (b) Flow cytometry of the frequencies of tdTomato+ IgG1+ class-switched plasmablasts/plasma cells (tdTomato+IgG1+B220loCD138hi) (upper panels), memory B cells (tdTomato+IgG1+B220hiCD138CD38+) and GC B cells (tdTomato+IgG1+B220hiCD138CD38) (lower panels) among splenic NP-specific donor cells (CD45.2+NP+) in NP-OVA immunized CD45.1+ wild-type recipient mice given transferred with CD45.2+ S1pr2-ERT2cre-tdTomato B1-8ge naive cells. At day 9 post-immunization, the mice were treated with anti-DEC205-OVA or anti-DEC205-CS at the indicated doses and tamoxifen for 3 days before analysis. (c) Ratios of tdTomato+NP+IgG1+ memory B cells to tdTomato+NP+IgG1+ GC B cells (left) and tdTomato+NP+IgG1+ plasmablasts/plasma cells to tdTomato+NP+IgG1+ GC B cells (right) from Supplemental Fig. 7b. Each symbol (c) represents an individual mouse; small horizontal lines indicate the mean. Data are representative of two independent experiments (b, c; mean in c).

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Shinnakasu, R., Inoue, T., Kometani, K. et al. Regulated selection of germinal-center cells into the memory B cell compartment. Nat Immunol 17, 861–869 (2016). https://doi.org/10.1038/ni.3460

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