IntroductionCD1a ϩ human dendritic cells (DCs) comprise 2 functionally distinct subsets including Langerhans-type DCs (LCs) and dermal/ interstitial DCs (DDC-IDCs). [1][2][3][4] Both DC subsets arise from monopoietic intermediates in cultures of human CD34 ϩ hematopoietic progenitor cells. LCs develop from early monocytic cells identified as lysozyme ϩ , CD14 ϩ/Ϫ , CD11b Ϫ in serum-free cultures of CD34 ϩ cells in response to TGF-1. [5][6][7][8][9][10] Conversely, DDC-IDCs arise from more differentiated CD14 ϩ /CD11b ϩ monocytes in progenitor cultures. 8,9 In both instances, CD1a ϩ DC generation is associated with repression of monocyte features by cultured cells.In vivo, LC differentiation requires epithelial TGF-1. 11,12 TGF-1 addition to single-cell cultures of CD34 ϩ cells induces LC colony formation at the expense of monocyte/macrophagecontaining colonies. 7 In line with an early lineage instructive effect of TGF-1 on monocyte/LC (M/LC) progenitors, CD34 ϩ cells rapidly lose TGF-1-responsive LC differentiation potential upon in vitro expansion. 13 Transcriptional mechanisms underlying TGF-1-dependent LC commitment remain unknown. Recently, positive transcriptional regulators of LC induction have been identified. The ETS-domain transcription factor PU.1 is essential for myelopoiesis and myeloid DC development. [14][15][16][17][18][19] Recent studies demonstrated that ectopic PU.1 expression induces CD1a ϩ LC-like cells from CD34 ϩ progenitor cells 20 and induces DC fate in transformed chicken myeloid progenitors as well as in the absence of cytokines in human HL60 myeloblast/promyelocytic cells and monocyte clones. 21 Similarly the helix-loop-helix (HLH) regulatory protein inhibitor of DNA binding/differentiation 2 (Id2) is required for LC differentiation in vivo. 22 Id2 is induced in day-10-generated DC progenitors in response to TGF-1 stimulation, 22 suggesting that Id2 is functionally involved in TGF-1-dependent LC generation.Given previous observations that TGF-1 instructs progenitor cells to undergo LC differentiation, 6,7 together with recent reports that PU.1 and Id2 are candidates as positive regulators of LC commitment, 20,22 we considered the study of a possible functional interrelationship between TGF-1 and these factors to be of substantial importance. For our analysis, we used a model in which TGF-1 stimulation instructs freshly isolated or short-term expanded (Ͻ 96 hours) CD34 ϩ hematopoietic progenitor cells to undergo LC commitment. We demonstrate that TGF-1 induces PU.1 and Id2 in CD34 ϩ progenitor cells undergoing LC commitment. Since omission of TGF-1 abrogates LC differentiation and progenitors, in turn, developed into monocytes, we studied whether ectopic PU.1 or Id2 functionally replaces exogenous TGF-1 for these effects. Id2 repressed monocyte differentiation and PU.1 strongly promoted LC differentiation. However, PU.1 strictly required exogenous TGF-1. Our data support a model suggesting that PU.1 is generally increased by stimuli that induce CD1a ϩ myeloid DC generatio...
IntroductionTwo in vitro systems for the generation of human dendritic cells (DCs) are widely used for basic and clinically oriented research: monocyte-derived DCs (moDCs) and hematopoietic progenitor cell (HPC)-derived DCs. In the first system, granulocytemacrophage colony-stimulating factor (GM-CSF) plus interleukin-4 (IL-4) are added to peripheral blood monocytes to generate moDCs. 1 This system is most widely applied for generating human DCs. In the second model, CD34 ϩ HPCs are stimulated in transforming growth factor 1 (TGF-1)-supplemented serumfree cultures (containing basic DC cytokines GM-CSF, tumor necrosis factor ␣ [TNF␣], stem cell factor [SCF] with or without Flt3L) for generating Langerhans cells (LCs), a DC subtype that resides within epithelial tissue. 2,3 Exclusion of TGF-1 from this latter culture system abrogates LC differentiation and de-represses a program of monocyte generation from CD34 ϩ cells. 3 When these latter HPC cultures are initiated in the presence of serum without TGF-1, 2 pathways of CD1a ϩ DCs are simultaneously generated, ie LCs and non-LC interstitial/dermal-type DCs. 4 These populations arise from 2 separate precursor pathways at culture day 5. A CD1a ϩ CD14 Ϫ precursor gives rise to LCs, whereas a CD1a Ϫ CD14 ϩ precursor can give rise to non-LC DCs, which share many features with moDCs generated from peripheral blood monocytes. 4,5 This CD1a Ϫ CD14 ϩ intermediate population can be further subdivided into 2 functional subsets based on CD11b (CD11b ϩ CD14 ϩ versus CD11b Ϫ CD14 ϩ monocytic cells). CD11b ϩ CD14 ϩ cells can be induced by GM-CSF plus IL-4 to develop into intDC/moDCs or by M-CSF to macrophage differentiation. Conversely, CD11b Ϫ CD14 ϩ intermediates, which represent early monocytic cells, retain LC differentiation capacity in the presence of TGF-1. 6 Therefore, a CD14 ϩ monocytic precursor can be induced to develop along 2 separate pathways in vitro depending on IL-4 (moDCs) versus TGF-1 (LCs) cytokine signals.IL-4 versus TGF-1 antagonize each other's function to induce moDCs versus LCs. Neutralizing anti-TGF-1 mAb represses LC generation in favor of CD14 ϩ monocyte generation. 7 Similarly, the addition of IL-4 to TGF-1-supplemented LC generation cultures of CD34 ϩ cells represses LC differentiation in favor of inducing non-LC DC differentiation. 7 Conversely, the addition of TGF-1 to GM-CSF plus IL-4-containing moDC cultures of peripheral blood monocytes polarizes these cells toward an LC-like phenotype. 8 In line with this, TGF-1 in the epidermal microenvironment is critical for LC differentiation in vivo. [9][10][11] Functional differences between moDCs versus LCs are increasingly recognized. However, very little is known about the molecular mechanisms controlling the lineage commitment of these cells to develop into different DC subsets (ie, LCs and non-LC moDCs).We recently performed mechanistic studies on the involvement of family members of the nuclear hormone receptor system, ie, retinoid X receptor-alpha (RXR␣) and vitamin D 3 receptor (VDR) i...
IntroductionImmature dendritic cells (DCs) such as epidermal/mucosal Langerhans cells (LCs) reside in peripheral tissues. Upon activation they migrate from peripheral sites to lymphoid organs and thereby acquire potent T-cell stimulatory capacity, a process referred to as DC maturation. 1,2 Various triggers are capable of inducing DC maturation. Pathogen recognition receptors (PRRs) such as Tolllike receptors (TLRs) induce pathogen-associated molecular pattern (PAMP)-dependent DC activation. Other stimuli are PAMP independent. These include inflammatory cytokines, environmental danger stimuli (eg, UV light and haptens), or dying cells. 2,3 Additionally, adhesion-dependent microenvironmental signals seem to counteract DC maturation, because epidermal shear stress itself triggers LC maturation. 4 Loss-of-function studies revealed that the classical NF-B pathway and the p38 MAPK cascade are fundamentally involved in or required for DC maturation. [5][6][7][8][9] Two NF-B signaling pathways are known. The classical NF-B pathway involves inhibitors of B (IBs), which upon phosphorylation and subsequent degradation release bound classical NF-B dimers (p65/p50 or c-rel/p50). 10 Inhibition of the classical NF-B pathway in human monocyte-derived DCs (moDCs) (eg, by adenoviral delivery of an IB␣ superrepressor [IB␣-SR] mutant) results in impaired DC maturation. [6][7][8] In the alternative (noncanonical) NF-B cascade, the p100 (NF-B2) molecule retains the alternative NF-B member RelB in the cytoplasm. Upon phosphorylation by the IB kinase 1 (IKK1), p100 is degraded to p52, RelB is released, and RelB/p52 dimers translocate to the nucleus. 10 Nuclear localization of RelB is considered a marker for mature DCs, because diverse maturation stimuli induce RelB translocation to the nuclei of DCs in vitro. 11 Similarly, in vivo nuclear RelB marks mature DCs in lymphoid organs and inflammatory sites such as rheumatoid arthritis lesions. 12,13 RelB is known to regulate DC development. RelBdeficient mice selectively lack myeloid-related CD8␣ Ϫ DCs but not LCs. 14 Similarly, differentiation of human CD11b ϩ interstitial-type DCs (intDCs) but not LCs from progenitor cells is inhibited by expressing a truncated p100 molecule that specifically captures RelB in the cytoplasm. 15 RelB deficiency was also shown to impair murine DC antigen presentation function in vivo. 16 Furthermore, DCs from p100-deficient mice, which have enhanced RelB activity but also lack p52, showed enhanced DC maturation. 17 However, expression of dominant negative NF-B-inducing kinase (NIK), an inducer of IKK1-mediated p100 processing, had no effect on human mo-DC maturation. 18 Therefore, while a critical function of RelB in DC subset development is well established, its function in DC maturation remains unclear.p38 mitogen-activated protein kinase (p38 MAPK) is an evolutionary highly conserved stress response pathway in eukaryotic cells. The p38 is activated by the upstream MAPK kinases MKK6 or MKK3 and is then translocated to the nucleus where it in turn phosphor...
Computational models of the auditory periphery are important tools for understanding mechanisms of normal and impaired hearing and for developing advanced speech and audio processing algorithms. However, the simulation of accurate neural representations entails a high computational effort. This prevents the use of auditory models in applications with real-time requirements and the design of speech enhancement algorithms based on efficient bio-inspired optimization criteria. Hence, in this work we propose and evaluate DNNbased approximations of a state-of-the-art auditory model. The DNN models yield accurate neurogram predictions for previously unseen speech signals with processing times shorter than signal duration, thus indicating their potential to be applied in real-time.
CD34+ cord blood progenitors can develop into interstitial/dermal (int) dendritic cells (DC) and Langerhans cells (LC). IL-4 induces common progenitors to differentiate into intDC and suppresses TGF-β1-dependent LC. The transcriptional mechanisms underlying DC versus LC development remain unclear. We found that the erythroid master transcription factor GATA-1 is differentially expressed in DC subtypes: LC were negative for GATA-1. However, GATA-1 was detected in CD34+-derived intDC and the related monocyte derived DC (moDC) with late kinetics and at low expression levels compared to erythroid cells. Induced expression of GATA-1 in DC/LC precursors promoted the formation of intDC and inhibited concomitant monocyte differentiation. Interestingly, GATA-1 and PU.1 are simultaneously expressed during moDC differentiation and both synergise in CD11b expression. Additionally, GATA-1 suppressed vitamin D3 receptor expression, which is a side-effect of moDC development. Taken together, these data indicate the crucial role of GATA-1 in DC development.
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