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CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease

Abstract

Dendritic cells (DCs) are 'professional' antigen-presenting cells that are key in the regulation of immune responses. Here we characterize a unique subset of tolerogenic DCs that expressed the chemokine receptor CCR9 and migrated to the CCR9 ligand CCL25, a chemokine linked to the homing of T cells and DCs to the gut. CCR9+ DCs were of the plasmacytoid DC (pDC) lineage, had an immature phenotype and rapidly downregulated CCR9 in response to maturation-inducing pDC-restricted Toll-like receptor ligands. CCR9+ pDCs were potent inducers of regulatory T cell function and suppressed antigen-specific immune responses both in vitro and in vivo, including inhibiting acute graft-versus-host disease induced by allogeneic CD4+ donor T cells in irradiated recipients. Our results identify a highly immunosuppressive population of pDCs present in lymphoid tissues.

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Figure 1: Tissue-specific CCR9 expression profiles of DCs.
Figure 2: CCR9+ DCs reside in the pDC compartment and have a mainly immature phenotype.
Figure 3: CCR9 expression allows pDCs to migrate to CCL25.
Figure 4: CCR9+ DCs downregulate CCR9 after being activated with pDC-specific TLR ligands.
Figure 5: CCR9+ DCs suppress immune responses in vivo and in vitro.
Figure 6: CCR9+ pDCs are potent inducers of regulatory T cells in vitro.
Figure 7: Lethal GVHD of C57BL/6 recipients induced by BALB/c CD4+CD25 effector T cells can be suppressed by coinjected C57BL/6 CCR9+ DCs.

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Acknowledgements

We thank L. Rott for assistance with flow cytometry and cell sorting; M. BenBarak for assistance with cytokine analysis with Luminex technology; and B. Zabel for discussions. Supported by the Arthritis Foundation (H.H.), the National Institutes of Health (AI07290 to H.H.; R03DK069395 to T.S.; K08DK069385 to A.H.; E.C.B.), the Wenner-Gren Foundation, Sweden (C.O.) and the Veterans Administration (E.C.B.).

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H.H. designed and did most of the experiments and wrote the manuscript; E.C.B. designed experiments and wrote the manuscript; T.S. prepared the irradiated mice, bone marrow and effector T cells in the GVHD studies and monitored the mice; A.H. was involved in the initial microarray studies and characterization of pDCs by flow cytometry; C.O. assisted with the TLR-activated pDC cytokine assays; J.P. helped with RNA preparation and microarray data analysis; and all authors discussed the results and read and provided comments on the manuscript.

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Correspondence to Husein Hadeiba or Eugene C Butcher.

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Hadeiba, H., Sato, T., Habtezion, A. et al. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat Immunol 9, 1253–1260 (2008). https://doi.org/10.1038/ni.1658

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