Abstract
Memory B cells (MBCs) are phenotypically and functionally diverse, but their developmental origins remain undefined. Murine MBCs can be divided into subsets by expression of CD80 and PD-L2. Upon re-immunization, CD80/PD-L2 double-negative (DN) MBCs spawn germinal center B cells (GCBCs), whereas CD80/PD-L2 double-positive (DP) MBCs generate plasmablasts but not GCBCs. Using multiple approaches, including generation of an inducible GCBC-lineage reporter mouse, we demonstrate in a T cell-dependent response that DN cells formed independently of the germinal center (GC), whereas DP cells exhibited either extrafollicular (DPEX) or GCBC (DPGC) origins. Chromatin and transcriptional profiling revealed similarity of DN cells with an early memory precursor. Reciprocally, GCBC-derived DP cells shared distinct genomic features with GCBCs, while DPEX cells had hybrid features. Upon restimulation, DPEX cells were more prone to divide, while DPGC cells differentiated toward IgG1+ plasmablasts. Thus, MBC functional diversity is generated through distinct developmental histories, which imprint characteristic epigenetic patterns onto their progeny, thereby programming them for divergent functional responses.
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Data availability
All bulk RNA-seq data have been deposited in the NCBI’s Gene Expression Omnibus (GEO) database and are publicly available under accession number GSE225748.
All bulk ATAC-seq data have been deposited in the NCBI GEO database and are publicly available under accession number GSE225672.
All scRNA-seq data have been deposited in the NCBI GEO database and are publicly available under accession number GSE225673.
The mm10 genome database (https://www.ncbi.nlm.nih.gov/assembly/GCF_000001635.20/) was used to align sequences for the RNA-seq analysis and to align sequencing reads for the ATAC-seq analysis.
All raw data and materials will be made available to investigators upon request. Source data are provided with this paper.
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Acknowledgements
We thank H. Singh for extensive discussions and critical reading of the manuscript; S. Naik (New York University), J. Sun (Sloan Kettering Institute) and C. Lau (Cornell University) for critical reading of the manuscript. We thank T. Marinov, M. Berkey, L. Conter and M. Price for technical support; University of Pittsburgh DLAR for excellent animal husbandry; members of the Shlomchik Lab Memory Group for suggestions and discussion throughout the development of this work. We thank the University of Pittsburgh Innovative Technology Development Core, led by S. Gingras, and the Mouse Embryo Services Core, led by C. Bi, for generating the GCET-TamCre mice. This research was supported in part by the University of Pittsburgh Center for Research Computing, RRID:SCR_022735, through the resources provided. Specifically, this work used the HTC cluster, which is supported by National Institutes of Health (NIH) award number S10OD028483. This research was also supported by NIH grants R01-AI43603 and R01-AI105018 to M.S. D.C. was supported by NIH T32 AI060525 (J. Flynn, principal investigator).
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D.C. performed most experiments and analyzed all experiments. S.J. performed some GCET-TamCre experiments, and F.W. performed the scRNA-seq experiment. F.W. drove the development of the GCET-TamCre mouse. K.H., under the supervision of S.K., performed Vh186.2 immunoglobulin somatic hypermutation analysis. S.S. completed quality checks and processed bioinformatic data and was advised by M.C. Bioinformatic analyses were performed by D.C. and S.S. The project was conceived by M.S. and D.C., who both designed experiments and interpreted data. M.S. and D.C. wrote the manuscript with input from all the authors.
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Extended data
Extended Data Fig. 1 Distinct transcriptomic and epigenetic profiles of FO NBCs and MBC subsets.
a, PCA plot of genes with expression of >= 0 log2 normalized reads in at least one cell type (n=3 per cell type). b, PCA plot of OCRs with accessibility of >= 1 log2 normalized reads in at least one cell type (n=2 per cell type). c,d, Boxplots showing relative PageRank score for TFs with higher (c) or lower (d) scores in all MBC subsets compared to FO naïve. Boxplots display median values and lower and upper quartiles, the ranges display min and maximum values. n= 2 per cell type.
Extended Data Fig. 2 DAR groups are enriched for distinct TF motifs.
a, Schematic of BALB/c transfer system using VPD-labeled donor cells. Mice were euthanized at days 2.5 and 11.5. b,c Representative flow plots depicting VPD-dilution of listed cell types compared to total transferred B cells in PBS control (unimmunized) at days 2.5 (b) and 11.5 (c). d, PCA plot of genes with expression of >= 0 log2 normalized reads in at least one cell type. e, PCA plot of OCRs with accessibility of >= 1 log2 normalized reads in at least one cell type. f, Ratio of Euclidean distance between DPs and EMPs to Euclidean distance between DNs and EMPs for given log2 FC RNA-seq differential expression thresholds, where Fig. 2c is the reference at abs(log2 FC DP vs DN) >=1. For Euclidean distance, a higher number indicates less similarity; if Euclidean distance ratio is > 1, numerator is less similar than denominator. g, Ratio of Euclidean distance between DNs and LZ GCs to Euclidean distance between DPs and LZ GCs for given log2 FC RNA-seq differential expression thresholds, where Fig. 2c is the reference at abs(log2 FC DP vs DN) >=1. h, Table of top TF motifs enriched in various DAR groups from Fig. 2d compared to background (all called peaks), computed via HOMER. Examples were manually chosen. p = p.value (calculated using cumulative binomial distribution), Motif Score = motif enrichment score above background, Known Motif = motif taken from HOMER database, TF Motif Name = specific TF and/or TF family, along with source if provided, % Coverage in DAR group = % of OCRs in a DAR group that have at least one motif sequence, % Coverage in all OCRs = % of all called OCRs that have at least one motif sequence. i, Heatmap depicting log2 normalized RNA expression of select TFs from Fig. 2f. j, Heatmap depicting all TF motifs with enrichment scores of log2 FC > = 1.4 above background, p. value <= 0.001 for any DAR group. Values shown are motif enrichment scores above background.
Extended Data Fig. 3 The GCET-TamCre is GCBC-specific.
a, Schematic to assess efficiency of GCBC-labeling and non-specific labeling in GCET-TamCre lineage tracing mice. Mice were given 1 mg tamoxifen on days 9, 10, and 11, post-immunization with NP-KLH and euthanized on day 13. b, Representative flow plots depicting YFP expression in NIP+ GCBCs and NIP+ non-GCBCs of corn oil control and tamoxifen-treated mice at day 13. c, Representative flow plots depicting YFP expression in plasmablasts of corn oil control and tamoxifen-treated mice at day 13. d, Representative flow plots depicting YFP expression in non-B cells of corn oil control and tamoxifen-treated mice at day 13. Left two columns depict a total T cell stain, while right 3 columns depict a myeloid lineage stain. e, Schematic to assess efficiency of B cell labeling GCET-TamCre lineage tracing mice. Naïve mice were given 1 mg tamoxifen every day for 3 consecutive days, whereas NP-KLH immunized mice were given 1 mg tamoxifen on days −0.5, 0.5, and 1.5 post-immunization. Mice were euthanized 1 day after final tamoxifen dose or 12 weeks later. f, Representative flow plots depicting YFP expression in naïve mice after 3 tamoxifen doses (top row) and YFP expression in early activated B cells at day 2.5 after 3 tamoxifen doses (bottom row). g, Representative flow plots depicting YFP expression in B cells of naïve mice after 3 tamoxifen doses and chasing out to 12 weeks (top row), YFP expression at week 12 post-immunization in mice not given tamoxifen (middle row), and YFP expression at 12 weeks post-immunization in mice given tamoxifen at days −0.5, 0.5, and 1.5 post-immunization.
Extended Data Fig. 4 Ly6D, PlexinB2, and CD73 can be used to identify GCBC-derived MBCs in WT BALB/c mice.
a, Flow cytometry plots depicting markers expressed by YFP+ MBCs in week 6 KP-KLH-immunized GCET-TamCre+/−R26-LSL-YFP+/− mice (from Fig. 3g; tamoxifen given on days 3–13). b-d, NIP+ Memory cells from directly immunized WT BALB/c mice 8 weeks post-NP-CGG immunization. b, Flow cytometry gating strategy to determine GC-derived MBCs (PlexinB2hiLy6DloCD73+) frequencies within CD80/PD-L2 MBC subsets. c, Flow cytometry gating strategy to determine frequencies of CD80/PD-L2 MBC subsets within total GC-derived MBCs (PlexinB2hiLy6DloCD73+). d, top: percent of GC-derived cells within each CD80/PD-L2 MBC subset; bottom: percent of each CD80/PD-L2 subset within total GC-derived MBCs (n = 5). Bars display mean ± s.d.
Extended Data Fig. 5 DPEX and DPGC have distinct functions in vivo.
a, Schematic for in vivo transfer and re-activation of 5,000 sorted IgG1− NIP+ MBC subsets. b, Day 4 in vivo data; left: NIP+CD19+CD45.1− cell counts per spleen, counted by flow cytometry (n = 14 for DPEX, n = 10 for DPGC, 4 independent experiments); right: Number of IgG1+ NIP+ spots per 1000 NIP+ cells (derived from left panel, (n = 11 for DPEX, n = 7 for DPGC, 3 independent experiments). c, Day 14 in vivo data; left: number of NIP+CD19+CD138−CD45.1−CD45.2+CD38−CD95+ GCBCs per spleen; right: number of NIP+CD19+CD138−CD45.1−CD45.2+CD38+ GCBCs per spleen. Both panels counted via flow cytometry (n = 5 for DN, n = 8 for DPEX, n = 6 for DPGC, 3 independent experiments). Bars display mean ± s.d. P-values were calculated using two-tailed Welch’s t-test (*P < = 0.05, **P < 0.01, ***P < 0.001). Actual p-values are listed in source data.
Extended Data Fig. 6 NP-Ficoll does not produce GCBC-derived MBCs.
a, Number of total MBCs at Day 5 (left) and Day 28 (right) between NP-CGG + PBS (day 5; n = 4, day 28, n = 5), NP-Ficoll + PBS (day 5; n = 6, day 28, n = 4), and NP-Ficoll + GK1.5 (day 5; n = 5, day 28, n = 7) treated mice from Fig. 5. b, Left/middle: Representative flow plots of pre-gated NIP+ B cells from Day 5 post-immunization for NP-KLH + PBS, NP-Ficoll + PBS, NP-KLH + GK1.5, and NP-Ficoll + GK1.5 treated GCET-TamCre+/−R26-LSL-YFP+/− mice. Mice were given one dose of tamoxifen on Day 3; right: Representative flow plots of pre-gated NIP + B cells from Day 28 post-immunization for NP-KLH + PBS, NP-Ficoll + PBS, NP-KLH + GK1.5, and NP-Ficoll + GK1.5 treated GCET-TamCre+/−R26-LSL-YFP+/− mice. Mice were given one dose of tamoxifen every other day from day 3–13. c, Number of YFP+ GCBCs (NIP+CD19+CD138−CD38−GL7+) per spleen at day 5 (n = 3 per group). d, left: Percent YFP+ of DP MBCs (NIP+CD19+CD138−CD38+GL7−), middle: Number of total DP MBCs per spleen, and right: Number of YFP+ DPs per spleen at day 28 (n = 3 per group). Bars display mean ± s.d. P-values were calculated using two-tailed Welch’s t-test (*P < = 0.05, **P < 0.01, ***P < 0.001). Actual p-values are listed in source data.
Extended Data Fig. 7 TI-derived MBCs are not GCBC-derived.
a, Number of total MBCs at Day 5 (left) and Day 28 (right) between NP-CGG + PBS control (day 5; n = 4, day 28, n = 6) and NP-CGG + GK1.5 + FGK (day 5; n = 6, day 28, n = 5) treated mice. b, Representative flow plots of NIP+ MBCs from BALBc transfer system under indicated immunizations at week 4. c, Number of MBC subsets per spleen for each indicated immunization. d, Representative flow plots of NIP+ MBCs from BALB/c transfer system under indicated immunizations at week 4, showing gating to determine GC-derived MBCs. e, left: percent of; right: number of; total MBCs displaying a GC-derived phenotype in the 4 different immunizations. For b-e, n = 3, except NP-CGG + FGK + GK1.5, where n = 4. Bars display mean ± s.d. P-values were calculated using two-tailed Welch’s t-test (*P < = 0.05). Actual p-values are listed in source data.
Extended Data Fig. 8 A shared CD80SP epigenetic signature can be found in TD and TI systems.
a, Examples of OCRs at Cd80 and Pdcd1lg2 that display a consistent pattern of accessibility in CD80SP MBCs within each system (NP-CGG + PBS, NP-Ficoll + GK1.5, NP-CGG + FGK + GK1.5, MBCs from day 28. n = 2 per cell types). b, GSEA plots using DARs between CD80SP MBCs and DN MBCs as genesets, showing all possible comparisons across all different systems. c, GSEA plots using DARs between CD80SP MBCs and DP MBCs as genesets, showing all possible comparisons across all different systems. Cutoff of log2FC >= 1, p-value <= 0.05 (calculated via two-tailed permutations), accessibility >= 2 log2 normalized counts was used for all genesets; the top 300 DARs, ordered by log2 FC, were used for the geneset unless total DARs were fewer than 300. Number of total DARs (in parentheses): NP-CGG; CD80SP > DN (884), CD80SP < DN (383), DP > CD80SP (93), DP < CD80SP (652). NP-Ficoll + GK1.5; CD80SP > DN (395), CD80SP < DN (83), DP > CD80SP (184), DP < CD80SP (37). NP-CGG + FGK + GK1.5; CD80SP > DN (1,332), CD80SP < DN (503), DP > CD80SP (499), DP < CD80SP (665).
Extended Data Fig. 9 TD-derived CD80SPs exhibit an inflammatory signature.
a, Bar graphs depicting OCRs that differ between DN MBCs and each other MBC subset. Top plot depicts OCRs lower in DNs than each MBC subset (x-axis); bottom plot depicts OCRs higher in DNs. Differential accessibility cutoff for each MBC subset compared to DNs is log2FC >= 1, FDR < = 0.05, and log2 accessibility >=1 normalized counts. b, Venn diagrams plotting the intersection of DARs that were more accessible in any MBC subset compared to DNs on the top and less accessible compared to DNs on the bottom, as enumerated in a. c, Bar graphs depicting OCRs that differ between DP MBCs and each other MBC subset. Top plot depicts OCRs lower in DPs than each MBC subset (x-axis); bottom plot depicts OCRs higher in DPs. Differential accessibility cutoff for each MBC subset compared to DPs is log2FC >= 1, FDR < = 0.05, and log2 accessibility >=1 normalized counts. d, Venn diagrams plotting the intersection of DARs that were more accessible in any MBC subset compared to DPs on the top and less accessible compared to DPs on the bottom, as enumerated in c. e, Select DARs near S1pr5 and Tbx21 showing specificity to CD80SP MBCs from the NP-CGG system. f, RNA expression heatmap (row z-scored) of select Tbet/ABC-associated genes among different systems and cell types (n = 3 for NP-CGG, n = 2 for other systems). g, PageRank score (z-scored) of Tbx21 from NP-CGG derived cell types.
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Callahan, D., Smita, S., Joachim, S. et al. Memory B cell subsets have divergent developmental origins that are coupled to distinct imprinted epigenetic states. Nat Immunol 25, 562–575 (2024). https://doi.org/10.1038/s41590-023-01721-9
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DOI: https://doi.org/10.1038/s41590-023-01721-9
