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

Nature volume 474, pages 216–219 (2011)Cite this article

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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.

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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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Author notes

  1. Toshiki I. Saito & Megan Sykes

    Present address: Present addresses: Department of Regenerative Medicine, Clinical Research Center, National Hospital Organization Nagoya Medical Center, 4-1-1 Sannomaru, Naka-ku, Nagoya Aichi 460-0001, Japan (T.I.S.); Columbia Center for Translational Immunology, Columbia University Medical Center, 650 W. 168th Street, BB 1512, New York, New York 10032, USA (M.S.).,

Authors and Affiliations

  1. Advanced Microscopy Program, Center for Systems Biology and Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, CPZN 8238, 185 Cambridge Street, Boston, Massachusetts 02114, USA ,

    Joji Fujisaki, Juwell Wu, Alicia L. Carlson & Charles P. Lin

  2. Harvard Stem Cell Institute, 42 Church Street, Cambridge, 02138, Massachusetts, USA

    Joji Fujisaki, Juwell Wu, Lev Silberstein, Cristina Lo Celso, David T. Scadden & Charles P. Lin

  3. Harvard-MIT Division of Health Sciences and Technology, 77 Massachusetts Avenue, E25-519, Cambridge, Massachusetts 02139, USA,

    Juwell Wu

  4. Center for Regenerative Medicine, Massachusetts General Hospital, 185 Cambridge Street, Boston, Massachusetts 02114, USA ,

    Lev Silberstein, Cristina Lo Celso & David T. Scadden

  5. Transplantation Institute and Department of Medicine, Beth Israel Deaconess Medical Center, Boston, 02215, Massachusetts, USA

    Prabhakar Putheti, Rafael Larocca, Wenda Gao & Terry B. Strom

  6. Bone Marrow Transplantation Section, Transplantation Biology Research Center, Massachusetts General Hospital, MGH-East, Bldg.149-5102 13th Street, Boston, Massachusetts 02129, USA ,

    Toshiki I. Saito & Megan Sykes

  7. Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan ,

    Hitoshi Tsuyuzaki & Tatsuyuki Sato

  8. Département de Physique, Génie Physique et Optique & Centre de Recherche Université Laval Robert-Giffard, Québec City, Québec G1J 2G3, Canada,

    Daniel Côté

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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.

Corresponding authors

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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