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In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche

Abstract

Stem cells reside in a specialized regulatory microenvironment or niche1,2, where they receive appropriate support for maintaining self-renewal and multi-lineage differentiation capacity1,2,3. The niche may also protect stem cells from environmental insults3 including cytotoxic chemotherapy and perhaps pathogenic immunity4. The testis, hair follicle and placenta are all sites of residence for stem cells and are immune-suppressive environments, called immune-privileged sites, where multiple mechanisms cooperate to prevent immune attack, even enabling prolonged survival of foreign allografts without immunosuppression4. We sought to determine if somatic stem-cell niches more broadly are immune-privileged sites by examining the haematopoietic stem/progenitor cell (HSPC) niche1,2,5,6,7 in the bone marrow, a site where immune reactivity exists8,9. We observed persistence of HSPCs from allogeneic donor mice (allo-HSPCs) in non-irradiated recipient mice for 30 days without immunosuppression with the same survival frequency compared to syngeneic HSPCs. These HSPCs were lost after the depletion of FoxP3 regulatory T (Treg) cells. High-resolution in vivo imaging over time demonstrated marked co-localization of HSPCs with Treg cells that accumulated on the endosteal surface in the calvarial and trabecular bone marrow. Treg cells seem to participate in creating a localized zone where HSPCs reside and where Treg cells are necessary for allo-HSPC persistence. In addition to processes supporting stem-cell function, the niche will provide a relative sanctuary from immune attack.

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Figure 1: Allo-HSPCs survive without immunosuppression for 30 days.
Figure 2: FoxP3 T reg cells accumulate on the endosteal surface, form clusters around adoptively transferred HSPCs and around allo-HSPCs that survive after 30 days.
Figure 3: Bone marrow T reg cells are critical in suppressing the rejection of allo-HSPCs in immune-competent recipients in an IL-10-dependent manner.

References

  1. Fuchs, E., Tumbar, T. & Guasch, G. Socializing with the neighbors: stem cells and their niche. Cell 116, 769–778 (2004)

    Article  CAS  Google Scholar 

  2. Li, L. & Xie, T. Stem cell niche: structure and function. Annu. Rev. Cell Dev. Biol. 21, 605–631 (2005)

    Article  CAS  Google Scholar 

  3. Arai, F. et al. Tie2/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche. Cell 118, 149–161 (2004)

    Article  CAS  Google Scholar 

  4. Niederkorn, J. Y. See no evil, hear no evil, do no evil: the lessons of immune privilege. Nature Immunol. 7, 354–359 (2006)

    Article  CAS  Google Scholar 

  5. Adams, G. B. & Scadden, D. T. The hematopoietic stem cell in its place. Nature Immunol. 7, 333–337 (2006)

    Article  CAS  Google Scholar 

  6. Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836–841 (2003)

    Article  CAS  ADS  Google Scholar 

  7. Calvi, L. M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003)

    Article  CAS  ADS  Google Scholar 

  8. Feuerer, M. et al. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nature Med. 9, 1151–1157 (2003)

    Article  CAS  Google Scholar 

  9. Joffre, O. et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nature Med. 14, 88–92 (2008)

    Article  CAS  Google Scholar 

  10. Zou, L. et al. Bone marrow is a reservoir for CD4+CD25+ regulatory T cells that traffic through CXCL12/CXCR4 signals. Cancer Res. 64, 8451–8455 (2004)

    Article  CAS  Google Scholar 

  11. Mazo, I. B. et al. Hematopoietic progenitor cell rolling in bone marrow microvessels: parallel contributions by endothelial selectins and vascular cell adhesion molecule 1. J. Exp. Med. 188, 465–474 (1998)

    Article  CAS  Google Scholar 

  12. Lo Celso, C. et al. Live-animal tracking of individual haematopoietic stem/progenitor cells in their niche. Nature 457, 92–96 (2009)

    Article  CAS  ADS  Google Scholar 

  13. Sipkins, D. A. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435, 969–973 (2005)

    Article  CAS  ADS  Google Scholar 

  14. Huang, Y. et al. Matching at the MHC class I K locus is essential for long-term engraftment of purified hematopoietic stem cells: a role for host NK cells in regulating HSC engraftment. Blood 104, 873–880 (2004)

    Article  CAS  Google Scholar 

  15. Jung, Y. et al. Regulation of SDF-1 (CXCL12) production by osteoblasts; a possible mechanism for stem cell homing. Bone 38, 497–508 (2006)

    Article  CAS  Google Scholar 

  16. Sugiyama, T., Kohara, H., Noda, M. & Nagasawa, T. Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches. Immunity 25, 977–988 (2006)

    Article  CAS  Google Scholar 

  17. Méndez-Ferrer, S. et al. Mesenchymal and haematopoietic stem cells form a unique bone marrow niche. Nature 466, 829–834 (2010)

    Article  ADS  Google Scholar 

  18. Welniak, L. A., Blazar, B. R. & Murphy, W. J. Immunobiology of allogeneic hematopoietic stem cell transplantation. Annu. Rev. Immunol. 25, 139–170 (2007)

    Article  CAS  Google Scholar 

  19. Bustin, S. A. Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. J. Mol. Endocrinol. 25, 169–193 (2000)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This work was supported by Bullock fellowship (to J.F.), the Harvard Stem Cell Institute and DoD W81XWH-10-1-0217 (to J.F. and C.P.L.), NIH HL097748 (to C.P.L.), HL97794 (to D.T.S.), CA111519 (to M.S.), AI041521 (to T.B.S), EMBO (to C.L.C.), HFSP (to C.L.C.), philanthropic sources (to D.T.S. and C.L.C.), and the National Institutes of Health. We acknowledge J. Zhao and D. Cao for cell sorting.

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Contributions

J.F. conceived the overall project, designed and performed experiments, analysed data and wrote the manuscript. J.W. and A.L.C. contributed to intravital imaging. L.S. and J.F. performed histology analysis. P.P. and J.F. performed qRT–PCR analysis. R.L. and J.F. performed FACS analysis using intracellular staining. W.G. performed mouse breeding. J.F., H.T. and T.S. performed HSPC isolation. D.C. generated software for IVM. T.I.S., C.L.C., M.S., T.B.S. and D.T.S. provided advice on the design of experiments. D.T.S. edited the manuscript. C.P.L. helped design experiments, supervised the overall study and wrote the manuscript.

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Correspondence to Joji Fujisaki or Charles P. Lin.

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The authors declare no competing financial interests.

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Fujisaki, J., Wu, J., Carlson, A. et al. In vivo imaging of Treg cells providing immune privilege to the haematopoietic stem-cell niche. Nature 474, 216–219 (2011). https://doi.org/10.1038/nature10160

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