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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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.).
The authors declare no competing financial interests.
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)
Phenotypic analyses of the expression of the CD62L ligand MAdCAM1 in HEV from tolerized, rejecting and naïve mice (n=2). (PDF 132 kb)
CCL17 expression in 1-week rejecting LN and splenic YAe+PDCA-1+ and YAe−PDCA-1+ cells (n=3). (PDF 135 kb)
SWAP-70 analysis of CD4+ T cells and CD11c+-B220+-PDCA-1+ cells by immunoblotting from wild-type mice (n=2). (PDF 100 kb)
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)
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)
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) doi:10.1038/ni1333
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