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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Banchereau, J. et al. Immunobiology of dendritic cells. Annu. Rev. Immunol. 18, 767–811 (2000).
Steinman, R.M., Hawiger, D. & Nussenzweig, M.C. Tolerogenic dendritic cells. Annu. Rev. Immunol. 21, 685–711 (2003).
van Duivenvoorde, L.M., van Mierlo, G.J., Boonman, Z.F. & Toes, R.E. Dendritic cells: vehicles for tolerance induction and prevention of autoimmune diseases. Immunobiology 211, 627–632 (2006).
Morelli, A.E. & Thomson, A.W. Tolerogenic dendritic cells and the quest for transplant tolerance. Nat. Rev. Immunol. 7, 610–621 (2007).
Charbonnier, L.M. et al. Immature dendritic cells suppress collagen-induced arthritis by in vivo expansion of CD49b+ regulatory T cells. J. Immunol. 177, 3806–3813 (2006).
Fu, F. et al. Costimulatory molecule-deficient dendritic cell progenitors (MHC class II+, CD80dim, CD86−) prolong cardiac allograft survival in nonimmunosuppressed recipients. Transplantation 62, 659–665 (1996).
Rastellini, C. et al. Granulocyte/macrophage colony-stimulating factor-stimulated hepatic dendritic cell progenitors prolong pancreatic islet allograft survival. Transplantation 60, 1366–1370 (1995).
Kim, S.H. et al. Effective treatment of established murine collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express IL-4. J. Immunol. 166, 3499–3505 (2001).
Kim, S.H., Kim, S., Oligino, T.J. & Robbins, P.D. Effective treatment of established mouse collagen-induced arthritis by systemic administration of dendritic cells genetically modified to express FasL. Mol. Ther. 6, 584–590 (2002).
Morelli, A.E. & Thomson, A.W. Dendritic cells: regulators of alloimmunity and opportunities for tolerance induction. Immunol. Rev. 196, 125–146 (2003).
Hackstein, H. & Thomson, A.W. Dendritic cells: emerging pharmacological targets of immunosuppressive drugs. Nat. Rev. Immunol. 4, 24–34 (2004).
Sato, K., Yamashita, N., Yamashita, N., Baba, M. & Matsuyama, T. Regulatory dendritic cells protect mice from murine acute graft-versus-host disease and leukemia relapse. Immunity 18, 367–379 (2003).
O'Connell, P.J. et al. Immature and mature CD8α+ dendritic cells prolong the survival of vascularized heart allografts. J. Immunol. 168, 143–154 (2002).
Liu, Y.J. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu. Rev. Immunol. 23, 275–306 (2005).
Colonna, M., Trinchieri, G. & Liu, Y.J. Plasmacytoid dendritic cells in immunity. Nat. Immunol. 5, 1219–1226 (2004).
Kuwana, M., Kaburaki, J., Wright, T.M., Kawakami, Y. & Ikeda, Y. Induction of antigen-specific human CD4+ T cell anergy by peripheral blood DC2 precursors. Eur. J. Immunol. 31, 2547–2557 (2001).
Martin, P. et al. Characterization of a new subpopulation of mouse CD8α+ B220+ dendritic cells endowed with type 1 interferon production capacity and tolerogenic potential. Blood 100, 383–390 (2002).
Bilsborough, J., George, T.C., Norment, A. & Viney, J.L. Mucosal CD8α+ DC, with a plasmacytoid phenotype, induce differentiation and support function of T cells with regulatory properties. Immunology 108, 481–492 (2003).
Arpinati, M. et al. Role of plasmacytoid dendritic cells in immunity and tolerance after allogeneic hematopoietic stem cell transplantation. Transpl. Immunol. 11, 345–356 (2003).
Fugier-Vivier, I.J. et al. Plasmacytoid precursor dendritic cells facilitate allogeneic hematopoietic stem cell engraftment. J. Exp. Med. 201, 373–383 (2005).
Abe, M., Wang, Z., de Creus, A. & Thomson, A.W. Plasmacytoid dendritic cell precursors induce allogeneic T-cell hyporesponsiveness and prolong heart graft survival. Am. J. Transplant. 5, 1808–1819 (2005).
Kohrgruber, N. et al. Survival, maturation, and function of CD11c− and CD11c+ peripheral blood dendritic cells are differentially regulated by cytokines. J. Immunol. 163, 3250–3259 (1999).
Kuwana, M. Induction of anergic and regulatory T cells by plasmacytoid dendritic cells and other dendritic cell subsets. Hum. Immunol. 63, 1156–1163 (2002).
Kunkel, E.J. et al. Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J. Exp. Med. 192, 761–768 (2000).
Uehara, S., Grinberg, A., Farber, J.M. & Love, P.E. A role for CCR9 in T lymphocyte development and migration. J. Immunol. 168, 2811–2819 (2002).
Salmi, M. & Jalkanen, S. Lymphocyte homing to the gut: attraction, adhesion, and commitment. Immunol. Rev. 206, 100–113 (2005).
Campbell, D.J. & Butcher, E.C. Rapid acquisition of tissue-specific homing phenotypes by CD4+ T cells activated in cutaneous or mucosal lymphoid tissues. J. Exp. Med. 195, 135–141 (2002).
Gilliet, M. et al. The development of murine plasmacytoid dendritic cell precursors is differentially regulated by FLT3-ligand and granulocyte/macrophage colony-stimulating factor. J. Exp. Med. 195, 953–958 (2002).
Vanbervliet, B. et al. The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12. J. Exp. Med. 198, 823–830 (2003).
Caux, C. et al. Dendritic cell biology and regulation of dendritic cell trafficking by chemokines. Springer Semin. Immunopathol. 22, 345–369 (2000).
Dieu, M.C. et al. Selective recruitment of immature and mature dendritic cells by distinct chemokines expressed in different anatomic sites. J. Exp. Med. 188, 373–386 (1998).
Weaver, C.T., Harrington, L.E., Mangan, P.R., Gavrieli, M. & Murphy, K.M. Th17: an effector CD4 T cell lineage with regulatory T cell ties. Immunity 24, 677–688 (2006).
Stockinger, B. & Veldhoen, M. Differentiation and function of Th17 T cells. Curr. Opin. Immunol. 19, 281–286 (2007).
Wendland, M. et al. CCR9 is a homing receptor for plasmacytoid dendritic cells to the small intestine. Proc. Natl. Acad. Sci. USA 104, 6347–6352 (2007).
Wurbel, M.A. et al. The chemokine TECK is expressed by thymic and intestinal epithelial cells and attracts double- and single-positive thymocytes expressing the TECK receptor CCR9. Eur. J. Immunol. 30, 262–271 (2000).
Zabel, B.A. et al. Human G protein-coupled receptor GPR-9–6/CC chemokine receptor 9 is selectively expressed on intestinal homing T lymphocytes, mucosal lymphocytes, and thymocytes and is required for thymus-expressed chemokine-mediated chemotaxis. J. Exp. Med. 190, 1241–1256 (1999).
Pabst, O. et al. Chemokine receptor CCR9 contributes to the localization of plasma cells to the small intestine. J. Exp. Med. 199, 411–416 (2004).
Bonasio, R. et al. Clonal deletion of thymocytes by circulating dendritic cells homing to the thymus. Nat. Immunol. 7, 1092–1100 (2006).
Zeng, D. et al. Unique patterns of surface receptors, cytokine secretion, and immune functions distinguish T cells in the bone marrow from those in the periphery: impact on allogeneic bone marrow transplantation. Blood 99, 1449–1457 (2002).
Hoffmann, P., Ermann, J., Edinger, M., Fathman, C.G. & Strober, S. Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J. Exp. Med. 196, 389–399 (2002).
Cohen, J.L., Trenado, A., Vasey, D., Klatzmann, D. & Salomon, B.L. CD4+CD25+ immunoregulatory T Cells: new therapeutics for graft-versus-host disease. J. Exp. Med. 196, 401–406 (2002).
Lohr, J., Knoechel, B., Wang, J.J., Villarino, A.V. & Abbas, A.K. Role of IL-17 and regulatory T lymphocytes in a systemic autoimmune disease. J. Exp. Med. 203, 2785–2791 (2006).
Murphy, W.J. et al. Differential effects of the absence of interferon-gamma and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J. Clin. Invest. 102, 1742–1748 (1998).
Yang, Y.G., Dey, B.R., Sergio, J.J., Pearson, D.A. & Sykes, M. Donor-derived interferon γ is required for inhibition of acute graft-versus-host disease by interleukin 12. J. Clin. Invest. 102, 2126–2135 (1998).
Harrington, L.E. et al. Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages. Nat. Immunol. 6, 1123–1132 (2005).
Park, H. et al. A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17. Nat. Immunol. 6, 1133–1141 (2005).
Morel, P.A., Vasquez, A.C. & Feili-Hariri, M. Immunobiology of DC in NOD mice. J. Leukoc. Biol. 66, 276–280 (1999).
Feili-Hariri, M. et al. Immunotherapy of NOD mice with bone marrow-derived dendritic cells. Diabetes 48, 2300–2308 (1999).
Popov, I. et al. Preventing autoimmune arthritis using antigen-specific immature dendritic cells: a novel tolerogenic vaccine. Arthritis Res. Ther. 8, R141 (2006).
Hochweller, K. & Anderton, S.M. Systemic administration of antigen-loaded CD40-deficient dendritic cells mimics soluble antigen administration. Eur. J. Immunol. 34, 990–998 (2004).
Maraskovsky, E. et al. Dramatic increase in the numbers of functionally mature dendritic cells in Flt3 ligand-treated mice: multiple dendritic cell subpopulations identified. J. Exp. Med. 184, 1953–1962 (1996).
Asselin-Paturel, C. et al. Mouse type I IFN-producing cells are immature APCs with plasmacytoid morphology. Nat. Immunol. 2, 1144–1150 (2001).
O'Keeffe, M. et al. Mouse plasmacytoid cells: long-lived cells, heterogeneous in surface phenotype and function, that differentiate into CD8+ dendritic cells only after microbial stimulus. J. Exp. Med. 196, 1307–1319 (2002).
Mach, N. et al. Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand. Cancer Res. 60, 3239–3246 (2000).
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.).
Author information
Authors and Affiliations
Contributions
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.
Corresponding authors
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni.1658
This article is cited by
-
Multivariate modeling of eosinophil markers and other cellular immune parameters associated with the development of chronic graft-versus-host disease
Bone Marrow Transplantation (2022)
-
The impact of the gut microbiota on T cell ontogeny in the thymus
Cellular and Molecular Life Sciences (2022)
-
CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation
Scientific Reports (2021)
-
STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function
Cellular & Molecular Immunology (2021)
-
Mechanistic Insights into Factor VIII Immune Tolerance Induction via Prenatal Cell Therapy in Hemophilia A
Current Stem Cell Reports (2019)