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B-1a lymphocytes promote oligodendrogenesis during brain development

Nature Neuroscience volume 21, pages 506–516 (2018)Cite this article

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Abstract

During brain development, the immune system mediates neurogenesis, gliogenesis and synapse formation. However, it remains unclear whether peripheral lymphocytes contribute to brain development. Here we identified the subtypes of lymphocytes that are present in neonatal mouse brains and investigated their functions. We found that B-1a cells, a subtype of B cells, were abundant in the neonatal mouse brain and infiltrated into the brain in a CXCL13–CXCR5-dependent manner. B-1a cells promoted the proliferation of oligodendrocyte-precursor cells (OPCs) in vitro, and depletion of B-1a cells from developing brains resulted in a reduction of numbers of OPCs and mature oligodendrocytes. Furthermore, neutralizing Fcα/μR, the receptor for the Fc region of IgM secreted by B-1a cells, inhibited OPC proliferation and reduced the proportion of myelinated axons in neonatal mouse brains. Our results demonstrate that B-1a cells infiltrate into the brain and contribute to oligodendrogenesis and myelination by promoting OPC proliferation via IgM–Fcα/μR signaling.

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Fig. 1: B cells of the B-1a subtype are abundant in neonatal mouse brains.
Fig. 2: Dynamics of transitional B cells in the blood and brains of neonatal mice.
Fig. 3: CXCL13–CXCR5 is associated with the infiltration of B-1a cells into the brain.
Fig. 4: B-1a cells promote the proliferation of OPCs in vitro.
Fig. 5: Depletion of B-1a cells suppresses oligodendrogenesis in the developing brain.
Fig. 6: Blockage of Fcα/μR reduces proliferation of OPCs and oligodendrocyte-lineage cells in vivo.
Fig. 7: Anti-Fcα/μR injection reduced the percentage of myelinated axons.

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Acknowledgements

We thank M. Fujitani (Hyogo College of Medicine) and Y. Hayano (Max Planck Florida Institute for Neuroscience) for technical advice regarding the in utero injection and T. Takeda, S. Kayama and Y. Doi (Osaka University) for providing CD19-Cre mice. Hanaichi UltraStructure Research Institute (Aichi, Japan) prepared the tissue sections for electron microscopy. This work was supported by a Grant-in-Aid for Scientific Research (S) from the Japan Society for the Promotion of Sciences (17H06178) to T.Y. and a Grand-in-Aid for Young Scientists (B) from the Japan Society for the Promotion of Sciences (16K18394) to S.T.

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Authors and Affiliations

  1. World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan

    Shogo Tanabe & Toshihide Yamashita

  2. Department of Molecular Neuroscience, Graduate School of Medicine, Osaka University, Osaka, Japan

    Toshihide Yamashita

  3. Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan

    Toshihide Yamashita

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  1. Shogo Tanabe
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S.T. designed and performed the experiments and analyzed the data. T.Y. coordinated and directed the project. All authors wrote the manuscript.

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Correspondence to Toshihide Yamashita.

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Integrated supplementary information

Supplementary Figure 1 Flow-cytometry analysis of B cells in neonatal brain.

Data from flow cytometry that are summarized in Fig. 1a–b. Mononuclear cells from embryonic days E16, E18, postnatal days P1, P5, P10, P14, P21, and postnatal week W8 were stained with anti-CD45, anti-CD19 and anti-CD45R antibodies and analyzed with a flow cytometer. (a) Gating strategy to analyze CD45+ leukocytes from brain. Mononuclear cells were gated with red line based on the level of SSC-A and FSC-A to exclude cell debris or dead cells, and CD45+ leukocytes were further gated with red rectangle. (b) Representative dot plots show the expression of CD19 and CD45R in CD45+ cells. CD19+ CD45R+ B cells were gated with black rectangles and representative numbers are the percentages of CD19+ CD45R+ B cells in CD45+ cells.

Supplementary Figure 2 Flow-cytometry data for dynamics of B cells in neonatal blood or brain.

(a) Gating methods of B cells from the neonatal blood. Gating methods of B cells from brain are described in Supplementary Figure 1. The mononuclear cells were gated with side scatter (SSC) and forward scatter (FSC) to exclude cell debris and dead cells. The CD45+ leukocytes were gated, and CD19+ CD45R+ double-positive cells were regarded as B cells. (b) Fluorescence-activated cell sorting (FACS) data for the expression of CD93 and CD23 in the B cells from neonatal blood from 3 independent experiments. Representative numbers in the dot plots are the percentages of cells located in the indicated area. (c) FACS data for the expression of CD93 and CD23 in the B cells from neonatal brain from 3 independent experiments.

Supplementary Figure 3 B cell depletion does not affect OPC proliferation in cerebral cortex or striatum.

(a-b) B cells were depleted by anti-BAFF-R-antibody administration at E16 and analyzed at P5. Representative images show immunohistochemistry for PDGFRα, Ki67 and Olig2 in cerebral cortex (a) and striatum (b) of control IgG or anti-BAFF-R treated mice brain. Scale bar: 100 μm. (c) Graph shows the percentage of Ki67+ cells in PDGFRα+ Olig2+ OPCs in cortex or striatum of control IgG- or anti-BAFF-R-treated mice (control IgG: n = 3, anti-BAFF-R: n = 3 from biologically independent experiments, 95% confidence interval of mean change = –10.26 to 14.49, p = 0.66 for cortex; 95% confidence interval of mean change = –4.556 to 7.550, p = 0.5301 for striatum, assessed by Two-sided Student’s t-test). NS: not significant. The data represent the mean ± SEM.

Supplementary Figure 4 B-cell depletion does not induce oligodendrocyte precursor cell death.

(a) B cells were depleted with anti-B-cell-activating factor receptor (BAFF-R)-antibody administration on embryonic day E16 and analyzed on postnatal day P5. Representative images show immunohistochemistry for cleaved caspase-3 (green) and platelet-derived growth factor receptor α (PDGFRα) (red) in the subventricular zone of the P5 brain. The inset image is a high magnification of the area in the white square. Scale bar: 50 μm, inset: 10 μm. (b) Graph shows the number of total cleaved caspase-3+ cells and PDGFRα, cleaved caspase-3 double-positive cells in the subventricular zone per mm2 (control IgG: n = 4, anti-BAFF-R: n = 4 from biologically independent experiments, 95% confidence interval of mean change = –20.03 to 17.59, p = 0.8789 for total cells; 95% confidence interval of mean change = –5.455 to 7.895, p = 0.6704 for OPC assessed by Two-sided Student’s t-test). Center line of box represents medium, upper and lower lines of box represent maximum and minimum values, respectively. NS: not significant. The data represent the mean ± SEM.

Supplementary Figure 5 Anti-B cell-activating factor receptor treatment reduces the accumulation of microglia in the subventricular zone.

(a) Immunohistochemical imaging for Iba-1 in the subventricular zone of the control IgG-treated or anti-BAFF-R-treated mouse brain on postnatal day P5. Scale bar: 50 μm. (b) Graph showing the number of Iba-1+ microglia in the subventricular zone per mm2 (Control IgG: n = 4, anti-BAFF-R: n = 3 from biologically independent experiments, 95% confidence interval of mean change = –133.6 to –6.375, F (2, 3) = 1.526, p = 0.0368, assessed by Two-sided Student’s t-test). *p <0.05. The data represent the mean ± SEM. (c–e) Immunohistochemical staining for glial fibrillary acidic protein (GFAP) in the subventricular zone (c), aldehyde dehydrogenase family 1 member L1 (Aldh1L1) in the cortex (d), and doublecortin in the lateral ventricle (e) from 3 independent experiments. Scale bar: 50 μm.

Supplementary Figure 6 OPCs at E18, astrocytes and neural progenitors at P5 do not express Fcα/μR.

(a-c) Immunohistochemistry for Fcα/μR and PDGFRα in the subventricular zone (a), cerebellum (b), and spinal cord (c) at E18 from 3 independent experiments. (d-f) Representative images show the immunohistochemistry for Fcα/μR, Aldh1l1 (d), GFAP (e) and doublecortin (f) in P5 brain from 3 independent experiments. Scale bar: 20 μm.

Supplementary Figure 7 Dynamics of injected antibody at P7 and P21.

The fluorescently labeled antibody with DyLight 650 was injected into the lateral ventricle in postnatal day P1 mice. Representative images showing fluorescence of DyLight 650 in the cerebrum at P7 (a) and P21 (b) from 7 independent experiments. Scale bar: 500 μm.

Supplementary Figure 8 Fcα/μR blockage has no effect on oligodendrogenesis of the spinal cord, but has a slight effect in the cerebellum.

(a) Representative images show the immunohistochemistry for Fcα/μR and PDGFRα in cerebellum and spinal cord at P5 from 3 independent experiments. Scale bar: 20 μm. (b) The Fcα/μR-neutralizing antibody was fluorescently labeled with DyLight 650, and injected into the lateral ventricle in postnatal day P1 mice from 6 independent experiments. Representative images showing fluorescence of DyLight 650 in the spinal cord (left) and the cerebellum (right) on P7. Scale bar: 250 μm. (c) Representative immunohistochemical staining for myelin basic protein (MBP) and homeobox protein Nkx2.2 in the spinal cord of control IgG-treated and anti-Fcα/μR-treated mice. The graph to the right of MBP shows the number of pixels per mm2. The graph to the right of Nkx2.2 shows the number of cells per mm2 (control IgG: n = 3, anti-Fcα/μR: n = 3 from biologically independent experiments, 95% confidence interval of mean change = –114.2 to 129.6, p = 0.8694 for MBP; 95% confidence interval of mean change = –111.9 to 257.6, p = 0.3349 for Nkx2.2 assessed by Two-sided Student’s t-test). Scale bar: 250 μm. (d) Immunohistochemistry for MBP and Nkx2.2 in the cerebellum of control IgG-treated and anti-Fcα/μR-treated mice. Graphs show pixel density for MBP and cell density for Nkx2.2 in each cerebellar folium (per mm2) (control IgG: n = 3, anti-Fcα/μR: n = 4 from biologically independent experiments, 95% confidence interval of mean change = –19.95 to 17.40, p = 0.8675 for MBP; 95% confidence interval of mean change = –253.5 to 16.28, p = 0.0329 for Nkx2.2, assessed by Two-sided Student’s t-test). Scale bar: 250 μm. NS: not significant, *p <0.05. The data represent the mean ± SEM.

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Tanabe, S., Yamashita, T. B-1a lymphocytes promote oligodendrogenesis during brain development. Nat Neurosci 21, 506–516 (2018). https://doi.org/10.1038/s41593-018-0106-4

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