The development of distinct dendritic cell (DC) subsets is regulated by cytokines. The ligand for the FMS-like tyrosine kinase 3 receptor (Flt3L) is necessary for plasmacytoid DC (pDC) and conventional DC (cDC) maturation. The cytokine GM-CSF inhibits Flt3L-driven pDC production while promoting cDC growth. We show that GM-CSF selectively utilized its signal transducer STAT5 to block Flt3L-dependent pDC development from the lineage-negative, Flt3+ (lin- Flt3+) bone-marrow subset. The signaling molecule STAT3, by contrast, was necessary for expansion of DC progenitors but not pDC maturation. In vivo, STAT5 suppressed pDC formation during repopulation of the DC compartment after bone-marrow ablation. GM-CSF-dependent STAT5 signaling rapidly extinguished pDC-related gene expression in lin- Flt3+ progenitors. Inspection of the Irf8 promoter revealed that STAT5 was recruited during GM-CSF-mediated suppression, indicating that STAT5 directly inhibited transcription of this critical pDC gene. Our results therefore show that GM-CSF controls the production of pDCs by employing STAT5 to suppress IRF8 and the pDC transcriptional network in lin- Flt3+ progenitors.
Plasmacytoid dendritic cells (pDCs) reside in bone marrrow and lymphoid organs in homeostatic conditions and typically secrete abundant quantities of type I interferons (IFNs) on Toll-like receptor triggering. Recently, a pDC population was identified within Peyer patches (PPs) of the gut that is distinguished by its lack of IFN production; however, the relationship of PP pDCs to pDCs in other organs has been unclear. We report that PP pDCs are derived from common DC progenitors and accumulate in response to Fms-like tyrosine kinase 3 ligand, yet appear divergent in transcription factor profile and surface marker phenotype, including reduced E2-2 and CCR9 expression. IntroductionPlasmacytoid dendritic cells (pDCs) were originally defined by their plasma cell-like morphology, surface marker profile, and ability to produce massive amounts of type I interferons (IFNs) in response to Toll-like receptor (TLR) triggering during viral infection. [1][2][3] IFNs regulate antiviral genes and activate effector cells to initiate adaptive immunity 4 ; thus, pDCs have been considered crucial to the host antiviral response. After TLR stimulation, pDCs mature into antigen-presenting cells (APCs) with up-regulated MHC class II and costimulatory molecules. 5 pDCs reside in bone marrow (BM) and lymphoid organs and regulate adaptive immunity by modulating T helper (Th) cell polarization (eg, induction of Th1 and Th2 and suppression of Th17 generation), activating CD8 ϩ cytotoxic T cells, and inducing regulatory T cell (Treg) function. [6][7][8] Aberrant pDC activity is linked to autoimmune and inflammatory diseases, including systemic lupus erythromatosus, psoriasis, and diabetes. 9,10 Moreover, IFN-␣ can be toxic in high concentrations and appears to contribute to autoimmunity when administered to humans 11,12 ; however, whether type I IFNs influence pDC function and/or development has been unclear.Recently, a pDC population was found in the subepithelial and interfollicular regions of the Peyer patches (PPs), 13 lymphoid organs adjacent to the intestine, suggesting potential contact with T lymphocytes infiltrating the gut. The PP pDC subset is distinguished from pDCs in other tissues by its inability to secrete abundant type I IFN in response to the TLR agonist CpG. Conditioning by factors that are highly expressed in mucosal tissues, including TGF-, IL-10, and prostaglandin E 2 , repressed IFN production from splenic pDCs, 13 suggesting that the microenvironment of the gut regulates PP pDC function. Although the developmental origin of PP pDCs and their relationship to pDCs found in BM and other lymphoid organs has remained unclear, these results suggest the potential for localized extracellular signals to regulate pDC function.Infection and other physiologic stresses stimulate cytokine output regionally and systemically. Certain cytokines, such as Fms-like tyrosine kinase 3 ligand (Flt3L) and GM-CSF, enhance proliferation of BM progenitor cells and support immune cell development, including pDCs and conventional DCs (cDCs). 1...
Plasmacytoid dendritic cells (pDCs) are the professional interferon (IFN)-producing cells of the immune system. pDCs specifically express Toll-like receptor (TLR)7 and TLR9 molecules and produce massive amounts of type I IFN by sensing microbial nucleic acids via TLR7 and TLR9. Here we report that protein kinase C and casein kinase substrate in neurons (PACSIN) 1, is specifically expressed in human and mouse pDCs. Knockdown of PACSIN1 by short hairpin RNA (shRNA) in a human pDC cell line significantly inhibited the type I IFN response of the pDCs to TLR9 ligand. PACSIN1-deficient mice exhibited normal levels of conventional DCs and pDCs, demonstrating that development of pDCs was intact although PACSIN1-deficient pDCs showed reduced levels of IFN-α production in response to both cytosine guanine dinucleotide (CpG)-oligonucleotide (ODN) and virus. In contrast, the production of proinflammatory cytokines in response to those ligands was not affected in PACSIN1-deficient pDCs, suggesting that PACSIN1 represents a pDC-specific adaptor molecule that plays a specific role in the type I IFN signaling cascade.
CD1d-restricted Vα14+ invariant NK T (iNKT) cells are a specialized αβ T cell subset that regulates both innate and adaptive immunity. Although costimulatory molecules are required for the activation of conventional T cells and for the development of Foxp3+ T cells, their role in iNKT cell regulation is unclear. Here we report that mice deficient in CD80/CD86 and/or B7h exhibit severe defects in thymic iNKT cell maturation, associated with largely reduced iNKT cell number in the thymus and the periphery. We show that costimulation is necessary for the optimal expansion of postselected NK1.1− immature iNKT cells in the thymus and for the proper expression of the maturation markers T-bet and CD122. Surprisingly, costimulatory molecules on both hemopoietic and nonhematopoietic cells are required for iNKT cell development. Our results thus demonstrate a previously unknown function of costimulation in the intrathymic development of iNKT cells, distinct from that of conventional T cells and regulatory T cells.
A vast majority of thymocytes are eliminated during T cell development by apoptosis. However, apoptotic thymocytes are not usually found in the thymus, indicating that apoptotic thymocytes must be eliminated rapidly by scavengers. Although macrophages and dendritic cells are believed to play such role, little is known about scavengers in the thymus. We found that CD4+/CD11b+/CD11c− cells were present in the thymus and that they expressed costimulatory molecules for T cell selection and possessed Ag-presenting activity. Moreover, these CD4+/CD11b+ cells phagocytosed apoptotic thymocytes much more efficiently than thymic CD4−/CD11b+ cells as well as activated peritoneal macrophages. CD4+/CD11b+ cells became larger along with thymus development, while no such change was observed in CD4−/CD11b+ cells. Finally, engulfed nuclei were frequently found in CD4+/CD11b+ cells. These results strongly suggest that thymic CD4+/CD11b+ cells are major scavengers of apoptotic thymocytes.
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