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Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts

Nature Immunology volume 7, pages 652–662 (2006)Cite this article

Abstract

The induction of alloantigen-specific unresponsiveness remains an elusive goal in organ transplantation. Here we identify plasmacytoid dendritic cells (pDCs) as phagocytic antigen-presenting cells essential for tolerance to vascularized cardiac allografts. Tolerizing pDCs acquired alloantigen in the allograft and then moved through the blood to home to peripheral lymph nodes. In the lymph node, alloantigen-presenting pDCs induced the generation of CCR4+CD4+CD25+Foxp3+ regulatory T cells (Treg cells). Depletion of pDCs or prevention of pDC lymph node homing inhibited peripheral Treg cell development and tolerance induction, whereas adoptive transfer of tolerized pDCs induced Treg cell development and prolonged graft survival. Thus, alloantigen-presenting pDCs home to the lymph nodes in tolerogenic conditions, where they mediate alloantigen-specific Treg cell development and allograft tolerance.

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Figure 1: Phagocytic pDCs cells take up and process antigen in donor cardiac allografts.
Figure 2: Alloantigen-presenting pDCs circulate systemically through blood.
Figure 3: YAe+ cells home to lymph nodes during tolerance and to the spleen during rejection.
Figure 4: 'Strategic' localization of YAe+ cells in the lymph nodes during tolerance.
Figure 5: Lymph node YAe+ pDCs induce the generation of Foxp3+CD4+CD25+ cells from of Foxp3−CD4+CD25− T cells.
Figure 6: Alloantigen-presenting pDC lymph node homing is necessary for Treg cell development and tolerance induction.

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Acknowledgements

We acknowledge the technical contributions of J. Llodra, H. Nikolayevskiy and S. Freeman, and discussions with M. Merad. Supported by National Institutes of Health (R01 AI41428, AI44929 and AI62765 to J.S.B.).

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Authors and Affiliations

  1. Department of Gene and Cell Medicine, Mount Sinai School of Medicine, New York, 10029-6574, New York, USA

    Jordi C Ochando, Chiho Homma, Yu Yang, Frank Tacke, Veronique Angeli, Yaozhong Ding, Rolf Jessberger, Gwendalyn J Randolph & Jonathan S Bromberg

  2. Hematology Center, Mount Sinai School of Medicine, New York, 10029-6574, New York, USA

    Andres Hidalgo

  3. Immunobiology Center, Mount Sinai School of Medicine, New York, 10029-6574, New York, USA

    Alexandre Garin

  4. Recanati/Miller Transplantation Institute, Mount Sinai School of Medicine, New York, 10029-6574, New York, USA

    Yansui Li, Peter Boros, Sergio A Lira & Jonathan S Bromberg

  5. Department of Physiological Chemistry, Dresden University of Technology, Dresden, Germany

    Rolf Jessberger

  6. Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, 20892-8003, Maryland, USA

    Giorgio Trinchieri

  7. Department of Surgery, Mount Sinai School of Medicine, New York, 10029-6574, New York, USA

    Jonathan S Bromberg

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Supplementary information

Supplementary Fig. 1

Real-time PCR analysis of type 1 interferon and Toll-like receptor (TLR) expression of blood circulating YAe+PDCA-1+ cells from tolerized and rejecting mice, compared to pDC from naïve animals (*, P>0.01 by one-way ANOVA) (n=3). (PDF 161 kb)

Supplementary Fig. 2

Phenotypic analyses of the expression of the CD62L ligand MAdCAM1 in HEV from tolerized, rejecting and naïve mice (n=2). (PDF 132 kb)

Supplementary Fig. 3

CCL17 expression in 1-week rejecting LN and splenic YAe+PDCA-1+ and YAe−PDCA-1+ cells (n=3). (PDF 135 kb)

Supplementary Fig. 4

SWAP-70 analysis of CD4+ T cells and CD11c+-B220+-PDCA-1+ cells by immunoblotting from wild-type mice (n=2). (PDF 100 kb)

Supplementary Fig. 5

Total percentage of CD4+ T cells and PDCA-1+ pDC in the LN or spleen of naïve Swap70—/— and wild-type (WT) mice (n=4). (PDF 152 kb)

Supplementary Fig. 6

Total percentage of CD4+ T cells and PDCA-1+ pDC in the LN of Swap70—/— and wild-type (WT) mice following transplantation and tolerogenic treatment with DST + anti-CD40L mAb (n=4), on day of rejection. (PDF 145 kb)

Supplementary Fig. 7

Flow cytometric analysis of the CD4+CD25+ T cell population in Swap70—/— and wild-type (WT) mice following transplantation and tolerogenic treatment with DST + anti-CD40L mAb (n=4), on day of rejection. (PDF 184 kb)

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Ochando, J., Homma, C., Yang, Y. et al. Alloantigen-presenting plasmacytoid dendritic cells mediate tolerance to vascularized grafts. Nat Immunol 7, 652–662 (2006). https://doi.org/10.1038/ni1333

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