scholarly journals Dendritic cell sphingosine-1-phosphate lyase regulates thymic egress

2016 ◽  
Vol 213 (12) ◽  
pp. 2773-2791 ◽  
Author(s):  
Jesus Zamora-Pineda ◽  
Ashok Kumar ◽  
Jung H. Suh ◽  
Meng Zhang ◽  
Julie D. Saba
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Stromal Cells ◽  
Thymic Epithelial Cells ◽  
Homeostatic Regulation ◽  
Wild Type ◽  
Central Tolerance ◽  
Corticomedullary Junction ◽  
Sphingosine 1 Phosphate ◽  
S1p Lyase

T cell egress from the thymus is essential for adaptive immunity and involves chemotaxis along a sphingosine-1-phosphate (S1P) gradient. Pericytes at the corticomedullary junction produce the S1P egress signal, whereas thymic parenchymal S1P levels are kept low through S1P lyase (SPL)–mediated metabolism. Although SPL is robustly expressed in thymic epithelial cells (TECs), in this study, we show that deleting SPL in CD11c+ dendritic cells (DCs), rather than TECs or other stromal cells, disrupts the S1P gradient, preventing egress. Adoptive transfer of peripheral wild-type DCs rescued the egress phenotype of DC-specific SPL knockout mice. These studies identify DCs as metabolic gatekeepers of thymic egress. Combined with their role as mediators of central tolerance, DCs are thus poised to provide homeostatic regulation of thymic export.

The Src-Like Adaptor Proteins, SLAP and SLAP2, Regulate Flt3-Dependent Dendritic Cell Development.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1535-1535
Author(s):  
Larissa Liontos ◽  
C. Jane McGlade
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
B Cell ◽  
Progenitor Cells ◽  
Adaptor Proteins ◽  
Cell Receptor ◽  
Sh2 Domain ◽  
Wild Type ◽  
Knock Out ◽  
Knock Out Mice

Abstract The Src-like Adaptor Proteins, SLAP and SLAP2, are hematopoietic adaptor proteins that have been previously shown to act as negative regulators of T- and B-cell signaling. SLAP and SLAP2 work in conjunction with the E3 ubiquitin ligase, c-Cbl, to down regulate the T-cell receptor and other components of the T- and B-cell receptor signaling pathways including ZAP-70 and Syk. SLAP and SLAP2 are expressed in many hematopoietic cell types, including progenitor cells that give rise to cells of both myeloid and lymphoid lineages. Recent evidence indicates a role for SLAP and SLAP2 in regulating hematopoietic receptor tyrosine kinase (RTK) signaling. We have shown that SLAP and SLAP2 interact with CSF-1R/Fms and demonstrated that SLAP2 negatively regulates CSF-1 dependent differentiation of FD-Fms cells. Our recent work demonstrates that both SLAP and SLAP2 interact with the Flt3 receptor in an SH2 domain dependent manner and the interaction was mapped to pY589 and pY591 within the juxtamembrane region of the receptor. To examine the role of SLAP and SLAP2 in Flt3 regulation and signaling in vivo, we utilized Flt3 ligand (Flt3L) to generate dendritic cells from mice lacking both SLAP and SLAP2. Slap1−/− Slap2−/− mice have impaired development of Flt3L-dependent CD11c+ bone marrow-derived dendritic cells (BMDC). In contrast to wild-type mice, Slap1−/− Slap2−/− mice produce 47% ± 9.7% less CD11c+ BMDC after 10 days in culture with Flt3L. Whether the reduction in BMDC numbers is indicative of a defect in the proliferation of Slap1−/−Slap2−/− progenitor cells in response to Flt3L is currently being explored. Although the absolute number of Flt3L-generated BMDC from Slap1−/−Slap2−/− mice is reduced, there are no major differences in the subtype, myeloid (70–90% CD11b+) and lymphoid (4–8% B220+), of DC produced between wild-type and double knock-out mice. To determine whether the reduction in dendritic cell numbers is specific to those generated with Flt3L, we generated BMDC using GM-CSF and IL-4. Both wild-type and double knock-out mice produce similar numbers of CD11c+ BMDC when this combination of cytokines is used. The maturation and activation of Flt3L-generated BMDC from Slap1−/−Slap2−/− mice is being investigated. These data indicate a novel role for SLAP and SLAP2 in the differentiation of Flt3L-dependent dendritic cells.

scholarly journals Measles Virus Targets DC-SIGN To Enhance Dendritic Cell Infection

2006 ◽  
Vol 80 (7) ◽  
pp. 3477-3486 ◽  
Author(s):  
Lot de Witte ◽  
Marion Abt ◽  
Sibylle Schneider-Schaulies ◽  
Yvette van Kooyk ◽  
Teunis B. H. Geijtenbeek
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Respiratory Tract ◽  
Immune Suppression ◽  
Measles Virus ◽  
Viral Transmission ◽  
Intercellular Adhesion Molecule ◽  
Wild Type ◽  
Cell Infection ◽  
Specific Receptors

ABSTRACT Dendritic cells (DCs) are involved in the pathogenesis of measles virus (MV) infection by inducing immune suppression and possibly spreading the virus from the respiratory tract to lymphatic tissues. It is becoming evident that DC function can be modulated by the involvement of different receptors in pathogen interaction. Therefore, we have investigated the relative contributions of different MV-specific receptors on DCs to MV uptake into and infection of these cells. DCs express the MV receptors CD46 and CD150, and we demonstrate that the C-type lectin DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN) is a novel receptor for laboratory-adapted and wild-type MV strains. The ligands for DC-SIGN are both MV glycoproteins F and H. In contrast to CD46 and CD150, DC-SIGN does not support MV entry, since DC-SIGN does not confer susceptibility when stably expressed in CHO cells. However, DC-SIGN is important for the infection of immature DCs with MV, since both attachment and infection of immature DCs with MV are blocked in the presence of DC-SIGN inhibitors. Our data demonstrate that DC-SIGN is crucial as an attachment receptor to enhance CD46/CD150-mediated infection of DCs in cis. Moreover, MV might not only target DC-SIGN to infect DCs but may also use DC-SIGN for viral transmission and immune suppression.

scholarly journals Mature Follicular Dendritic Cell Networks Depend on Expression of Lymphotoxin β Receptor by Radioresistant Stromal Cells and of Lymphotoxin β and Tumor Necrosis Factor by B Cells

1999 ◽  
Vol 189 (1) ◽  
pp. 159-168 ◽  
Author(s):  
Robert Endres ◽  
Marat B. Alimzhanov ◽  
Thomas Plitz ◽  
Agnes Fütterer ◽  
Marie H. Kosco-Vilbois ◽  
...  
Keyword(s):  
Dendritic Cell ◽  
Tumor Necrosis Factor ◽  
Stromal Cells ◽  
Tumor Necrosis ◽  
Cell Types ◽  
Follicular Dendritic Cell ◽  
Wild Type ◽  
Humoral Immune ◽  
Follicular Dendritic ◽  
Necrosis Factor

The formation of germinal centers (GCs) represents a crucial step in the humoral immune response. Recent studies using gene-targeted mice have revealed that the cytokines tumor necrosis factor (TNF), lymphotoxin (LT) α, and LTβ, as well as their receptors TNF receptor p55 (TNFRp55) and LTβR play essential roles in the development of GCs. To establish in which cell types expression of LTβR, LTβ, and TNF is required for GC formation, LTβR−/−, LTβ−/−, TNF−/−, B cell–deficient (BCR−/−), and wild-type mice were used to generate reciprocal or mixed bone marrow (BM) chimeric mice. GCs, herein defined as peanut agglutinin–binding (PNA+) clusters of centroblasts/centrocytes in association with follicular dendritic cell (FDC) networks, were not detectable in LTβR−/− hosts after transfer of wild-type BM. In contrast, the GC reaction was restored in LTβ−/− hosts reconstituted with either wild-type or LTβR−/− BM. In BCR−/− recipients reconstituted with compound LTβ−/−/BCR−/− or TNF−/−/BCR−/− BM grafts, PNA+ cell clusters formed in splenic follicles, but associated FDC networks were strongly reduced or absent. Thus, development of splenic FDC networks depends on expression of LTβ and TNF by B lymphocytes and LTβR by radioresistant stromal cells.

Autonomous versus dendritic cell-dependent contributions of medullary thymic epithelial cells to central tolerance

2011 ◽  
Vol 32 (5) ◽  
pp. 188-193 ◽  
Author(s):  
Ludger Klein ◽  
Maria Hinterberger ◽  
Julia von Rohrscheidt ◽  
Martin Aichinger
Keyword(s):  
Dendritic Cell ◽  
Epithelial Cells ◽  
Thymic Epithelial Cells ◽  
Central Tolerance ◽  
Medullary Thymic Epithelial Cells

Transition from cMyc to L-Myc during dendritic cell development coordinated by rising levels of IRF8

2021 ◽  
Vol 219 (2) ◽  
Author(s):  
David A. Anderson ◽  
Feiya Ou ◽  
Sunkyung Kim ◽  
Theresa L. Murphy ◽  
Kenneth M. Murphy
Keyword(s):  
Cell Cycle ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Cell Development ◽  
Mutant Mice ◽  
Classical Type ◽  
Wild Type ◽  
Cell Cycle Proteins ◽  
Plasmacytoid Dcs

During dendritic cell (DC) development, Myc expression in progenitors is replaced by Mycl in mature DCs, but when and how this transition occurs is unknown. We evaluated DC development using reporters for MYC, MYCL, and cell cycle proteins Geminin and CDT1 in wild-type and various mutant mice. For classical type 1 dendritic cells (cDC1s) and plasmacytoid DCs (pDCs), the transition occurred upon their initial specification from common dendritic cell progenitors (CDPs) or common lymphoid progenitors (CLPs), respectively. This transition required high levels of IRF8 and interaction with PU.1, suggesting the use of EICEs within Mycl enhancers. In pDCs, maximal MYCL induction also required the +41kb Irf8 enhancer that controls pDC IRF8 expression. IRF8 also contributed to repression of MYC. While MYC is expressed only in rapidly dividing DC progenitors, MYCL is most highly expressed in DCs that have exited the cell cycle. Thus, IRF8 levels coordinate the Myc-Mycl transition during DC development.

scholarly journals Development of Dendritic Cells from GM-CSF-/-Miceinvitro: GM-CSF Enhances Production and Survival of Cells

2001 ◽  
Vol 8 (2) ◽  
pp. 133-146 ◽  
Author(s):  
Keping Ni ◽  
Helen C. O'Neill
Keyword(s):  
Dendritic Cells ◽  
Stromal Cells ◽  
Critical Factor ◽  
Wild Type ◽  
Gm Csf ◽  
T Cell Stimulation ◽  
Multiple Cultures ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Antigen Presenting

The production of dendritic cells (DC) from haemopoietic progenitors maintained in long term stroma-dependent cultures (LTC) of spleen or bone marrow (BM) occurs independently of added granulocyte/macrophage colony stimulating factor (GM-CSF). The possibility that cultures depend on endogenous GM-CSF produced in low levels was tested by attempting to generate LTC from spleen and BM of GM-CSF-/-mice. Multiple cultures from GM-CSF-/-and wild type mice were established and compared for cell production. GM-CSF-/-LTC developed more slowly, but by 16 weeks produced cells resembling DC in numbers comparable to wild type cultures. LTC maintained distinct populations of small and large cells, the latter resembling DC. Cells collected from GM-CSF-/-LTC were capable antigen presenting cells (APC) for T cell stimulation and morphologically resembled DC. Large cells expressed the CD11b, CD11c, CD86, 33D1 and Dec-205 markers of DC. Addition of GM-CSF to GM-CSF-/-LTC increased the proportion of large, mature DC present in culture. Stromal cells from GM-CSF-/-LTC could support the differentiation of DC from early progenitors maintained in LTC without addition of GM-CSF. However, GM-CSF is not a critical factor in theinvitrogeneration of DC from progenitors. It can, however, substitute for stromal cells in increasing the survival of mature DC.

scholarly journals Spatial Mapping of Myelopoiesis Reveals the Bone Marrow Niche for Monocyte Dendritic Cell Progenitors

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 528-528
Author(s):  
Jizhou Zhang ◽  
Qingqing Wu ◽  
Courtney Johnson ◽  
André Olsson ◽  
Anastasiya Slaughter ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Dendritic Cells ◽  
Dendritic Cell ◽  
Stromal Cells ◽  
Myeloid Cell ◽  
Osteoblastic Cells ◽  
Random Simulation ◽  
Fold Reduction ◽  
Classical Monocytes ◽  
Myeloid Progenitors

Monocytes, macrophages and dendritic cells are indispensable for innate immunity. Myelopoiesis takes place in the bone marrow (BM) through differentiation of a common myeloid progenitor into monocyte dendritic cell progenitors (MDP) or granulocyte monocyte progenitors (GMP). MDP differentiate into myeloid progenitors (MoP) or common dendritic progenitors (cDP) that give rise to monocytes or dendritic cells (DC) repectively. GMP can also generate neutrophil-like monocytes via an intermediate monocyte progenitor [MP; Immunity. 2017 47(5):890] and neutrophils via a granulocyte progenitor (GP). CSF1 (M-CSF) is the key cytokine that regulates monopoiesis, CSF1 loss causes profound defects in monocyte, dendritic cell, macrophage and osteoclast generation. Classical studies using Csf1-/- chimeric mice demonstrated that CSF1 is produced by BM stromal cells. However the identity of these CSF1-producing cells is unknown. A major limitation is the lack of immunofluorescence protocols to map progenitor interaction with candidate niches. We have found that CD11b-Ly6C-CD117+CD115+ cells are MDP; Lin-Ly6C-CD117+CD16/32+CD115- cells are GMP; CD11b-Ly6C+CD117+CD115+ are MP/MoP; CD11b-Ly6C+CD117+CD115- are GP; CD11b+CD115+Ly6Chi and CD11b+CD115+Ly6Clo cells are classical and non-classical monocytes; and MHCIIhi reticular cells are DC. We used the markers above to map the 3D position of every myeloid cell in the sternum and assessed the relationships between myeloid progenitors, their offspring and candidate niches in situ with single cell resolution. To test whether the interactions observed were specific we obtained the X, Y and Z coordinates for every hematopoietic cell in the sternum (detected using αCD45 and αTer119). We then used these coordinates to randomly place each type of myeloid cell, at the same frequencies found in vivo, through the BM to generate a random distribution for each myeloid cell type. HSC localize to sinusoidal, arteriolar and endosteal niches. However, myeloid progenitors are exclusively perisinusoidal (mean MDP distance to sinusoids, arterioles, and endosteum observed 5, 134, and 105μm vs 9, 86, and 69µm in the random simulation). Myeloid progenitors rarely localize with HSC indicating that progenitors abandon the HSC niche upon differentiation. Strikingly, we found that granulopoiesis, monopoiesis and DCpoiesis occur in distinct sinusoidal locations and that MDP are tightly associated with sinusoids, dendritic cells and Ly6Clo monocytes (2.0 DC and 4.4 Ly6Clo monocytes observed within 50µm of an MDP vs 0.9 DC and 1.8 Ly6Clo monocytes in the random simulation p=0.02 and p<0.0001) but not with MoP/MP or Ly6Chi classical monocytes. The results above suggest that the stromal cells that provide the signals that regulate MDP will localize to the sinusoids. Analyses of Csf1 expression in two recently published scRNAseq studies of BM stroma showed that perivascular stromal cells and osteoblastic cells are the major CSF1 sources with sinusoidal endothelial cells expressing much lower levels. Csf1 deletion in perivascular cells using LepR-cre mice and in osteoblastic cells using Ocn-cre mice did not impact Ly6Chi classical or Ly6Clo non-classical monocytes in peripheral blood. We also did not find any defects in BM MDP, GMP, MoP numbers or colony forming activity or in monocyte or dendritic cell numbers. In sharp contrast we found that conditional Csf1 deletion in endothelial cells using Cdh5-cre mice led to a 3.9-fold defect in Ly6Clo non-classical monocytes in the blood (1.89 vs 0.47 x105/ml in the +/- controls vs Cdh5-cre:Csf1-/Δ mice; p=0.03). In the BM these mice showed a 1.4 reduction in MDP numbers (0.72 vs 0.5x104/femur; p=0.04) further compounded by a 2.7-fold loss in MDP-derived CFU-M (22 vs 8 colonies/100 cells; p=0.009) indicating a dramatic reduction in MDP function. This in turn led to a 2.3-fold reduction in Ly6Clo non classical monocytes (9.5 vs 4.1x104/femur; p=0.01) and a 1.2-fold reduction in cDC (2.7 vs 2.1 x104cDC/femur p=0.005). In summary we have imaged for the first time myeloid progenitors; mapped their differentiation into mature myeloid cells; quantified their interaction with candidate niche cells; showed that sinusoids are the exclusive site of monocyte and dendritic cell production; and demonstrated that endothelial cells are a niche that regulates MDP numbers and function via CSF1. Disclosures No relevant conflicts of interest to declare.

Evidence for a link between histone deacetylation and Ca2+ homoeostasis in sphingosine-1-phosphate lyase-deficient fibroblasts

2012 ◽  
Vol 447 (3) ◽  
pp. 457-464 ◽  
Author(s):  
Katja Ihlefeld ◽  
Ralf Frederik Claas ◽  
Alexander Koch ◽  
Josef M. Pfeilschifter ◽  
Dagmar Meyer zu Heringdorf
Keyword(s):  
Kinase Inhibitor ◽  
Trichostatin A ◽  
Histone Deacetylation ◽  
Wild Type ◽  
Embryonic Fibroblasts ◽  
Hdac Activity ◽  
Histone 3 ◽  
Sphingosine 1 Phosphate ◽  
Wild Type Mefs ◽  
S1p Lyase

Embryonic fibroblasts from S1P (sphingosine-1-phosphate) lyase-deficient mice [Sgpl1−/− MEFs (mouse embryonic fibroblasts)] are characterized by intracellular accumulation of S1P, elevated cytosolic [Ca2+]i and enhanced Ca2+ storage. Since S1P, produced by sphingosine kinase 2 in the nucleus of MCF-7 cells, inhibited HDACs (histone deacetylases) [Hait, Allegood, Maceyka, Strub, Harikumar, Singh, Luo, Marmorstein, Kordula, Milstein et al. (2009) Science 325, 1254–1257], in the present study we analysed whether S1P accumulated in the nuclei of S1P lyase-deficient MEFs and caused HDAC inhibition. Interestingly, nuclear concentrations of S1P were disproportionally elevated in Sgpl1−/− MEFs. HDAC activity was reduced, acetylation of histone 3-Lys9 was increased and the HDAC-regulated gene p21 cyclin-dependent kinase inhibitor was up-regulated in these cells. Furthermore, the expression of HDAC1 and HDAC3 was reduced in Sgpl1−/− MEFs. In wild-type MEFs, acetylation of histone 3-Lys9 was increased by the S1P lyase inhibitor 4-deoxypyridoxine. The non-specific HDAC inhibitor trichostatin A elevated basal [Ca2+]i and enhanced Ca2+ storage, whereas the HDAC1/2/3 inhibitor MGCD0103 elevated basal [Ca2+]i without influence on Ca2+ storage in wild-type MEFs. Overexpression of HDAC1 or HDAC2 reduced the elevated basal [Ca2+]i in Sgpl1−/− MEFs. Taken together, S1P lyase-deficiency was associated with elevated nuclear S1P levels, reduced HDAC activity and down-regulation of HDAC isoenzymes. The decreased HDAC activity in turn contributed to the dysregulation of Ca2+ homoeostasis, particularly to the elevated basal [Ca2+]i, in Sgpl1−/− MEFs.

scholarly journals Correction of lung inflammation in a F508del CFTR murine cystic fibrosis model by the sphingosine-1-phosphate lyase inhibitor LX2931

2016 ◽  
Vol 311 (5) ◽  
pp. L1000-L1014 ◽  
Author(s):  
Mieke Veltman ◽  
Marta Stolarczyk ◽  
Danuta Radzioch ◽  
Gabriella Wojewodka ◽  
Juan B. De Sanctis ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Dendritic Cells ◽  
Mutant Mouse ◽  
Abnormal Behavior ◽  
Mouse Lung ◽  
Lung Pathology ◽  
Cell Counts ◽  
Mouse Tissues ◽  
Sphingosine 1 Phosphate ◽  
S1p Lyase

Progressive lung disease with early onset is the main cause of mortality and morbidity in cystic fibrosis patients. Here we report a reduction of sphingosine-1-phosphate (S1P) in the lung of unchallenged Cftr tm1EUR F508del CFTR mutant mice. This correlates with enhanced infiltration by inducible nitric oxide synthase (iNOS)-expressing granulocytes, B cells, and T cells. Furthermore, the ratio of macrophage-derived dendritic cells (MoDC) to conventional dendritic cells (cDC) is higher in mutant mouse lung, consistent with unprovoked inflammation. Oral application of a S1P lyase inhibitor (LX2931) increases S1P levels in mutant mouse tissues. This normalizes the lung MoDC/cDC ratio and reduces B and T cell counts. Lung granulocytes are enhanced, but iNOS expression is reduced in this population. Although lung LyC6+ monocytes are enhanced by LX2931, they apparently do not differentiate to MoDC and macrophages. After challenge with bacterial toxins (LPS-fMLP) we observe enhanced levels of proinflammatory cytokines TNF-α, KC, IFNγ, and IL-12 and the inducible mucin MUC5AC in mutant mouse lung, evidence of deficient resolution of inflammation. LX2931 does not prevent transient inflammation or goblet cell hyperplasia after challenge, but it reduces MUC5AC and proinflammatory cytokine levels toward normal values. We conclude that lung pathology in homozygous mice expressing murine F508del CFTR, which represents the most frequent mutation in CF patients, is characterized by abnormal behavior of infiltrating myeloid cells and delayed resolution of induced inflammation. This phenotype can be partially corrected by a S1P lyase inhibitor, providing a rationale for therapeutic targeting of the S1P signaling pathway in CF patients.

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