Tissue-specific differentiation of a circulating CCR9- pDC-like common dendritic cell precursor.

The ontogenic relationship between the common dendritic cell (DC) progenitor (CDP), the committed conventional DC precursor (pre-cDC), and cDC subpopulations in lymphoid and nonlymphoid tissues has been largely unraveled. In contrast, the sequential steps of plasmacytoid DC (pDC) development are less defined, and it is unknown at which developmental stage and location final commitment to the pDC lineage occurs. Here we show that CCR9(-) pDCs from murine BM which enter the circulation and peripheral tissues have a common DC precursor function in vivo in the steady state, in contrast to CCR9(+) pDCs which are terminally differentiated. On adoptive transfer, the fate of CCR9(-) pDC-like precursors is governed by the tissues they enter. In the BM and liver, most transferred CCR9(-) pDC-like precursors differentiate into CCR9(+) pDCs, whereas in peripheral lymphoid organs, lung, and intestine, they additionally give rise to cDCs. CCR9(-) pDC-like precursors which are distinct from pre-cDCs can be generated from the CDP. Thus, CCR9(-) pDC-like cells are novel CDP-derived circulating DC precursors with pDC and cDC potential. Their final differentiation into functionally distinct pDCs and cDCs depends on tissue-specific factors allowing adaptation to local requirements under homeostatic conditions.

[1]  A. Schlitzer,et al.  Identification of CCR9- murine plasmacytoid DC precursors with plasticity to differentiate into conventional DCs. , 2011, Blood.

[2]  A. Brooks,et al.  Cross-presentation of viral and self antigens by skin-derived CD103+ dendritic cells , 2009, Nature Immunology.

[3]  Yong‐jun Liu,et al.  Cell-intrinsic role for IFN-α-STAT1 signals in regulating murine Peyer patch plasmacytoid dendritic cells and conditioning an inflammatory response. , 2011, Blood.

[4]  X. Qin,et al.  The signal transducer STAT5 inhibits plasmacytoid dendritic cell development by suppressing transcription factor IRF8. , 2008, Immunity.

[5]  B. Pulendran,et al.  Mice lacking flt3 ligand have deficient hematopoiesis affecting hematopoietic progenitor cells, dendritic cells, and natural killer cells. , 2000, Blood.

[6]  Steffen Jung,et al.  Intestinal lamina propria dendritic cell subsets have different origin and functions. , 2009, Immunity.

[7]  D. Kelvin,et al.  In Situ Replication of Immediate Dendritic Cell (DC) Precursors Contributes to Conventional DC Homeostasis in Lymphoid Tissue1 , 2006, The Journal of Immunology.

[8]  Markus G. Manz,et al.  Development of Monocytes, Macrophages, and Dendritic Cells , 2010, Science.

[9]  G. Trinchieri,et al.  The Development of Murine Plasmacytoid Dendritic Cell Precursors Is Differentially Regulated by FLT3-ligand and Granulocyte/Macrophage Colony-Stimulating Factor , 2002, The Journal of experimental medicine.

[10]  G. Trinchieri,et al.  Plasmacytoid dendritic cells in immunity , 2004, Nature Immunology.

[11]  K. Lewis,et al.  Continuous expression of the transcription factor e2-2 maintains the cell fate of mature plasmacytoid dendritic cells. , 2010, Immunity.

[12]  F. Ginhoux,et al.  Origin and functional heterogeneity of non‐lymphoid tissue dendritic cells in mice , 2010, Immunological reviews.

[13]  B. Blom,et al.  Development of human plasmacytoid dendritic cells depends on the combined action of the basic helix‐loop‐helix factor E2‐2 and the Ets factor Spi‐B , 2008, European journal of immunology.

[14]  Atsushi Miyawaki,et al.  Visualizing Spatiotemporal Dynamics of Multicellular Cell-Cycle Progression , 2008, Cell.

[15]  M. Manz,et al.  The concerted action of GM-CSF and Flt3-ligand on in vivo dendritic cell homeostasis. , 2009, Blood.

[16]  M. Colonna,et al.  A cell-surface molecule selectively expressed on murine natural interferon-producing cells that blocks secretion of interferon-alpha. , 2004, Blood.

[17]  Eric Vivier,et al.  Novel insights into the relationships between dendritic cell subsets in human and mouse revealed by genome-wide expression profiling , 2008, Genome Biology.

[18]  Steffen Jung,et al.  CX3CR1+ CD8α+ dendritic cells are a steady-state population related to plasmacytoid dendritic cells , 2010, Proceedings of the National Academy of Sciences.

[19]  D. Jarrossay,et al.  Identification of clonogenic common Flt3+M-CSFR+ plasmacytoid and conventional dendritic cell progenitors in mouse bone marrow , 2007, Nature Immunology.

[20]  M. Colonna,et al.  Siglec-H is an IPC-specific receptor that modulates type I IFN secretion through DAP12. , 2006, Blood.

[21]  G. Trinchieri,et al.  Mouse Strain Differences in Plasmacytoid Dendritic Cell Frequency and Function Revealed by a Novel Monoclonal Antibody , 2003, The Journal of Immunology.

[22]  J. Villadangos,et al.  Antigen-presentation properties of plasmacytoid dendritic cells. , 2008, Immunity.

[23]  R. Schreiber,et al.  Bone Marrow Stromal Cell Antigen 2 Is a Specific Marker of Type I IFN-Producing Cells in the Naive Mouse, but a Promiscuous Cell Surface Antigen following IFN Stimulation1 , 2006, The Journal of Immunology.

[24]  J. Hamilton.  Colony-stimulating factors in inflammation and autoimmunity , 2008, Nature Reviews Immunology.

[25]  R. Steinman,et al.  SnapShot: Dendritic Cells , 2011, Cell.

[26]  M. Mihm,et al.  Differences in dendritic cells stimulated in vivo by tumors engineered to secrete granulocyte-macrophage colony-stimulating factor or Flt3-ligand. , 2000, Cancer research.

[27]  D. Koller,et al.  The Immunological Genome Project: networks of gene expression in immune cells , 2008, Nature Immunology.

[28]  T. Korn,et al.  Antigen Targeting to Plasmacytoid Dendritic Cells via Siglec-H Inhibits Th Cell-Dependent Autoimmunity , 2011, The Journal of Immunology.

[29]  G. Adler,et al.  Enteric Flora Expands Gut Lamina Propria CX3CR1+ Dendritic Cells Supporting Inflammatory Immune Responses under Normal and Inflammatory Conditions , 2010, The Journal of Immunology.

[30]  G. Trinchieri,et al.  Plasmacytoid dendritic cells mediate oral tolerance. , 2008, Immunity.

[31]  H. Lehr,et al.  CCL17 promotes intestinal inflammation in mice and counteracts regulatory T cell-mediated protection from colitis. , 2012, Gastroenterology.

[32]  Li Wu,et al.  Intrasplenic steady-state dendritic cell precursors that are distinct from monocytes , 2006, Nature Immunology.

[33]  Melanie Bahlo,et al.  Development of plasmacytoid and conventional dendritic cell subtypes from single precursor cells derived in vitro and in vivo , 2007, Nature Immunology.

[34]  Meredith O'Keeffe,et al.  M-CSF: a novel plasmacytoid and conventional dendritic cell poietin. , 2008, Blood.

[35]  A. Schlitzer,et al.  Antigen Delivery to Plasmacytoid Dendritic Cells via BST2 Induces Protective T Cell-Mediated Immunity , 2011, The Journal of Immunology.

[36]  Manfred Lehner,et al.  Transcription Factor E2-2 Is an Essential and Specific Regulator of Plasmacytoid Dendritic Cell Development , 2008, Cell.

[37]  A. Rudensky,et al.  In Vivo Analysis of Dendritic Cell Development and Homeostasis , 2009, Science.

[38]  S. Watowich,et al.  Mechanisms regulating dendritic cell specification and development , 2010, Immunological reviews.

[39]  C. Begley,et al.  Hematopoietic and lung abnormalities in mice with a null mutation of the common beta subunit of the receptors for granulocyte-macrophage colony-stimulating factor and interleukins 3 and 5. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[40]  F. Ginhoux,et al.  Origin of the lamina propria dendritic cell network. , 2009, Immunity.

[41]  F. Ginhoux,et al.  The origin and development of nonlymphoid tissue CD103+ DCs , 2009, The Journal of experimental medicine.

[42]  W. Reith,et al.  MHC class II–restricted antigen presentation by plasmacytoid dendritic cells inhibits T cell–mediated autoimmunity , 2010, The Journal of experimental medicine.