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Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches

Abstract

Beyond its established function in hematopoiesis, the bone marrow hosts mature lymphocytes and acts as a secondary lymphoid organ in the initiation of T cell and B cell responses. Here we report the characterization of bone marrow–resident dendritic cells (bmDCs). Multiphoton imaging showed that bmDCs were organized into perivascular clusters that enveloped blood vessels and were seeded with mature B lymphocytes and T lymphocytes. Conditional ablation of bmDCs in these bone marrow immune niches led to the specific loss of mature B cells, a phenotype that could be reversed by overexpression of the antiapoptotic factor Bcl-2 in B cells. The presence of bmDCs promoted the survival of recirculating B cells in the bone marrow through the production of macrophage migration–inhibitory factor. Thus, bmDCs are critical for the maintenance of recirculating B cells in the bone marrow.

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Figure 1: Characterization of the mouse bmDC compartment.
Figure 2: The bmDCs are organized into unique perivascular clusters that define bone marrow immune niches containing B cells and T cells.
Figure 3: Conditional ablation of bmDCs.
Figure 4: The maintenance of recirculating mature B cells in the bone marrow requires bmDCs.
Figure 5: The bmDCs provide survival signals to mature B cells in the bone marrow.
Figure 6: The survival of mature B cells in bone marrow is independent of BAFF-producing bmDCs.
Figure 7: The survival of mature B cells in bone marrow requires MIF-producing bmDCs.

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Acknowledgements

We thank G. Shakhar, A. Mahler and the members of the Jung laboratory for critical reading of the manuscript, and Y. Chermesh and O. Amram for animal husbandry. Supported by the Israeli Science Foundation (S.J. and I.S), the Moross Institute (S.J. and I.S.) and the Minerva Foundation (I.S.).

Author information

Authors and Affiliations

Authors

Contributions

Y.P.-J. made the initial observation of the diminution in B cells; A.S. and Y.P.-J. did flow cytometry; A.S. and V.K. did imaging analysis; R.K. provided technical help; and I.S. and S.J. designed the study and wrote the paper.

Corresponding author

Correspondence to Steffen Jung.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 (PDF 863 kb)

Supplementary Video 1

Perivascular cluster of BM-resident DC (bmDCs). Two-photon microscopic analysis of cranial BM cavity of Cx3cr1gfp/+ mouse. Immediately before imaging, the animal received an intravenous injection of TRITC-dextran (150 kDa; Sigma) to visualize bone marrow vasculature. BmDCs (green), blood vessels (red). (MOV 780 kb)

Supplementary Video 2

Perivascular cluster of BM-resident DC (bmDCs). Two-photon microscopic analysis of cranial BM cavity of Cx3cr1gfp/+ mouse. Immediately before imaging, the animal received an intravenous injection of TRITC-dextran (150 kDa; Sigma) to visualize bone marrow vasculature. BmDCs (green), blood vessels (red). (MOV 2386 kb)

Supplementary Video 3

Perivascular cluster of BM-resident DC (bmDCs). Two-photon microscopic analysis of cranial BM cavity of Cx3cr1gfp/+ mouse. Immediately before imaging, the animal received an intravenous injection of TRITC-dextran (150 kDa; Sigma) to visualize bone marrow vasculature. BmDCs (green), blood vessels (red). (MOV 3587 kb)

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Sapoznikov, A., Pewzner-Jung, Y., Kalchenko, V. et al. Perivascular clusters of dendritic cells provide critical survival signals to B cells in bone marrow niches. Nat Immunol 9, 388–395 (2008). https://doi.org/10.1038/ni1571

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