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Surface phenotypes of naive and memory B cells in mouse and human tissues

Nature Immunology volume 23, pages 135–145 (2022)Cite this article

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Abstract

Memory B cells (MBCs) protect the body from recurring infections. MBCs differ from their naive counterparts (NBCs) in many ways, but functional and surface marker differences are poorly characterized. In addition, although mice are the prevalent model for human immunology, information is limited concerning the nature of homology in B cell compartments. To address this, we undertook an unbiased, large-scale screening of both human and mouse MBCs for their differential expression of surface markers. By correlating the expression of such markers with extensive panels of known markers in high-dimensional flow cytometry, we comprehensively identified numerous surface proteins that are differentially expressed between MBCs and NBCs. The combination of these markers allows for the identification of MBCs in humans and mice and provides insight into their functional differences. These results will greatly enhance understanding of humoral immunity and can be used to improve immune monitoring.

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Fig. 1: Discovery of surface markers differentially regulated between MBCs and NBCs by mouse LEGENDScreen analysis.
Fig. 2: Discovery of differentially regulated surface markers between MBCs and NBCs by human LEGENDScreen analysis.
Fig. 3: Venn diagram of highly expressed surface markers on human and mouse NBCs and MBCs.
Fig. 4: Summary of marker expression revealed by human and mouse LEGENDScreen analysis.
Fig. 5: Combinations of surface markers that allow for the identification of mouse MBCs.
Fig. 6: Surface markers differentially regulated on NBCs and MBCs across human tissues and donors.
Fig. 7: Combinations of surface markers that allow for the identification of human MBCs across tissues.
Fig. 8: Pathway enrichment analysis of markers differentially regulated between MBCs and NBCs, as revealed by LEGENDScreen analysis.

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Data availability

All data are available upon request. Flow cytometry files of LEGENDScreen assays were deposited and are publicly available at http://flowrepository.org with the accession numbers FR-FCM-Z4LQ (mouse LEGENDScreen) and FR-FCM-Z4LS (human LEGENDScreen). Source data are provided with this paper.

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Acknowledgments

We thank D. Carpenter for organ acquisition, the transplant coordinators at LiveOnNY for tissues from organ donors and members of the laboratory of D. Farber at Columbia University for providing access to human organ donor tissue samples. We thank M. Berkey for supporting experimental procedures. We thank BioLegend, in particular A. Cornett and N. Lucas, for providing reagents. This work was funded by National Institutes of Health, National Institute of Allergy and Infectious Diseases (NIH/NIAID) grants R01 AI043603 (M.J.S.) and P01 AI106697 (M.J.S. and D.L.F.).

Author information

Author notes

  1. These authors contributed equally: Nadine M. Weisel, Stephen M. Joachim.

  2. These authors jointly supervised this work: Florian J. Weisel, Mark J. Shlomchik.

Authors and Affiliations

  1. Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA

    Nadine M. Weisel, Stephen M. Joachim, Shuchi Smita, Derrick Callahan, Rebecca A. Elsner, Laura J. Conter, Maria Chikina, Florian J. Weisel & Mark J. Shlomchik

  2. Department of Computational and Systems Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Shuchi Smita & Maria Chikina

  3. Department of Microbiology and Immunology, Columbia University Medical Center, New York, NY, USA

    Donna L. Farber

  4. Department of Surgery, Columbia University Medical Center, New York, NY, USA

    Donna L. Farber

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Contributions

N.M.W. and S.M.J. contributed equally to this work. M.J.S. and F.J.W. designed research and are equal senior authors. F.J.W., N.M.W., S.M.J. and L.J.C. performed experiments and analyzed data. D.L.F. and R.A.E. gave conceptual advice. S.S., D.J.C. and M.M.C. performed computational analysis. F.J.W. and M.J.S. wrote the manuscript.

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Correspondence to Mark J. Shlomchik.

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Peer review information Nature Immunology thanks the anonymous reviewers for their contribution to the peer review of this work. L. A. Dempsey was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.

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Extended data

Extended Data Fig. 1 Surface markers differentially expressed on human and mouse NBCs and MBCs, in support of Fig. 3.

Differentially regulated surface markers as in Fig. 3 are sorted based on the ratio of the MFI of MBCs to NBCs. a, MFI ratio of MBCs to NBCs in humans (mean of three donors (D182, D185 and D186)). b, MFI ratio MBCs to NBCs in mice. Red and blue dots depict higher expression on MBCs or NBCs, respectively. Plot was built using ggplot2 (version 3.2.1) in R (version 3.6.1).

Extended Data Fig. 2 Validation of surface markers differentially regulated on mouse NBCs and MBCs, in support of Figs. 3 and 4.

Histograms of flow cytometric expression of 24 depicted surface markers on MBCs (red) and NBCs (blue). MBCs were identified as CD45.2+NIP+CD19+ live singlets on splenocytes of transfer recipients (seven females 39 weeks old 31 weeks after immunization plus three males 34 weeks old 23 weeks after immunization) and splenic B cells of CD45.1 naive B1-8i+/− BALB/cJ mice (three males 11 weeks old plus two males, 9 weeks old) were mixed into the staining to serve as NBC, identified by their CD45 allotype mark. Cells were stained with Murine Stain 3 (Supplementary Tables 5 and 6). The FMO control for the PE channel is shown in the bottom right histogram.

Extended Data Fig. 3 Validation of surface markers differentially regulated on human NBCs and MBCs, in support of Figs. 3 and 4.

Cryopreserved human splenocytes were stained with Stain 2, Stain 3, Stain 4 or Stain 5 (Supplementary Tables 3 and 4) for flow cytometric analysis. Shown are histograms of the expression of 16 depicted surface markers on MBCs (CD19+CD27+, red) and NBCs (CD19+CD27−, blue). All markers were validated on three individual donor spleens listed in the tables below the histograms.

Extended Data Fig. 4 Combinations of surface markers that allow for the identification of mouse MBCs and NBCs in the C57BL/6 background, in support of Fig. 5.

Direct immunization (left): single-cell suspensions of indicated tissues from three male C57BL/6 WT (CD45.2, 12 weeks old, 4 weeks after immunization) mice were analyzed at day 28 after i.p. immunization with 100 µg NP-KLH. 5 × 106 cells were mixed with 1 × 106 cells of corresponding tissues of one naive male C57BL/6 CD45.1 congenic mouse (8 weeks old) to allow for the simultaneous identification of MBCs and their comparable naive counterparts in a single staining tube. MBCs and NBCs were identified as described in Supplementary Fig. 8a, and displayed data are concatenated of three individual samples. OT-II adoptive transfer system (right): single-cell suspensions of indicated tissues from five individual OT-II adoptive transfer recipients (males, 12 weeks old, 4 weeks after immunization) were analyzed at day 28 after i.p. immunization with 50 µg NP-CGG. 5 × 106 cells were mixed with 1 × 106 cells of corresponding tissues of one male naive C57BL/6 WT (CD45.2) mouse (7 weeks old) to allow for the simultaneous identification of MBCs and their comparable naive counterparts in a single staining tube. Cells were stained with Murine Stain 5 (Supplementary Tables 5 and 6). MBCs (red) and NBCs (blue) were identified as described in Supplementary Fig. 8b, and displayed data are concatenated of five individual samples. Shown are contour plots of pairwise combinations of CD205/CD274, CD81/CD11a and CD267/CD180 as in Fig. 5, which can be used to distinguish MBCs and NBCs across tissues.

Extended Data Fig. 5 Surface markers differentially regulated on NBCs versus MBCs across human tissues, in support of Fig. 6.

Single-cell suspensions of spleen (SP), blood (B), BM, LN, intestinal tissue (gut) and tonsil (T) were stained for flow-cytometric analysis using Stain 2 and Stain 4 (Supplementary Tables 3 and 4). The left panel shows the summary of the differences in MFI between CD19+CD27+ B cells and CD19+CD27− B cells (ΔMFI) for the depicted surface markers. For CD74 and CD119, spleen (n = 23 in red), blood (n = 7 in blue), BM (n = 9 in magenta), LN (n = 6 in green), gut (n = 3 in brown) and tonsil (n = 2 in black) samples were analyzed. For CD218a, spleen (n = 21 in red), blood (n = 10 in blue), BM (n = 10 in magenta), LN (n = 8 in green), gut (n = 8 in brown) and tonsil (n = 2 in black) samples were analyzed. For CD370, spleen (n = 21 in red), blood (n = 10 in blue), BM (n = 10 in magenta), LN (n = 8 in green), gut (n = 8 in brown) and tonsil (n = 2 in black) samples were analyzed. Bars are mean and error bars are ± standard deviation. The right panel shows example histograms for depicted surface markers of CD19+CD27− B cells (blue) and CD19+CD27+ B cells (red) across tissues of D260. Stars indicate significant differences in ΔMFI of indicated tissues compared to spleen using the unpaired two-tailed t test with Welch’s correction. ***P < 0.001, ****P < 0.0001. Exact significant P values for comparison between spleen and the indicated tissue for each marker are for CD74: all tissues, P < 0.0001; for CD119, blood, BM and gut,P < 0.0001, LN P = 0.0006 and tonsil P = 0.1112; for CD218a, blood and BM P < 0.0001, gut P = 0.0001 and tonsil P = 0.1047; and for CD370, blood, LN, gut and tonsil P = 0.0002 and BM P = 0.0003.

Source data

Extended Data Fig. 6 Expression of surface markers CD11a and CD200 on human splenic MBCs and NBCs separated by Ig isotype, in support of Fig. 7.

Splenic single-cell suspensions were stained for depicted markers (Stain 5, Supplementary Tables 3 and 4). Overlayed histograms for expression of CD11a (top) or CD200 (bottom) of either total CD27− and CD27+ (first row), or specific Ig isotypes for CD27− overlayed with total CD27+ (row 2, CD27− IgM/D; row 3, CD27− IgG; and row 4, CD27− IgA) are shown for six individual donors (D192, D215, D228, D333, D365 and D388). CD19+CD27+ MBCs are in red, and CD19+CD27− NBCs are in blue. The last rows of each panel show a summary of the CD27− isotypes analyzed (IgM/D, green; IgG, blue; and IgA, orange) in direct comparison with the total CD27− B cells (red).

Supplementary information

Supplementary Information

Supplementary Figures 1–10 and Supplementary Tables 1–6.

Reporting Summary

Source data

Source Data Fig. 6

Delta MFI for different tissues for depicted markers..

Source Data Extended Data Fig. 5

Delta MFI for different tissues for depicted markers

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Weisel, N.M., Joachim, S.M., Smita, S. et al. Surface phenotypes of naive and memory B cells in mouse and human tissues. Nat Immunol 23, 135–145 (2022). https://doi.org/10.1038/s41590-021-01078-x

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