Engagement Of Fc Epsilon RI On Human Monocytes Induces The Production Of IL-10 And Prevents Their Differentiation In Dendritic Cells
Novak N, Bieber T, Katoh N
J Immunol. 2001 Jul 15;167(2):797-804
University of Bonn, Department of Dermatology, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany
The local Cytokine environment and the presence of stimulatory signals determine whether circulating Monocytes will finally acquire characteristics of Dendritic Cells (DCs) or Macrophages.
Because FcepsilonRI expressed on professional APCs, e.g., Monocytes and DCs, has been suggested to play a key role in the pathophysiology of Atopic Diseases, we evaluated the effect of receptor ligation on the generation of Monocyte-derived DCs (MoDCs).
Aggregation of FcepsilonRI at the initiation of the IL-4-GM-CSF-driven differentiation resulted in the emergence of Macrophage-like cells with a strong expression of the Mannose Receptor and a low level of CD1a and the DC-specific markers CD83 and the Actin-bundling protein (p55).
These cells sustained the ability to take up FITC-labeled Escherichia coli by Phagocytosis and were significantly less efficient in stimulating purified Allogeneic T-Cells.
In addition, receptor ligation of FcepsilonRI at the beginning of the culture prevented the generation of MoDCs, mainly due to a dramatic increase in the IL-10 production.
These results suggest that FcepsilonRI aggregation prevents the generation of CD1a+ MoDCs and imply a novel pivotal function of this receptor in modulating the differentiation of Monocytes.
Stimulatory And Inhibitory Differentiation Of Human Myeloid Dendritic Cells
Chakraborty A, Li L, Chakraborty NG, Mukherji B
Clin Immunol. 2000 Feb;94(2):88-98
University of Connecticut School of Medicine, Department of Medicine, Farmington, Connecticut 06030-3210, USA
Dendritic Cells (DCs) play a critical obligate role in presenting Antigens to T-Cells for activation. In the process, upon Antigen capture, DCs undergo maturation and become more stimulatory.
Human Myeloid DCs can be generated from various sources, including blood, bone marrow, and CD34+ Stem Cells.
As such, plastic-adherent Monocytes from circulation have served as a ready source for generating Myeloid DCs in culture in Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and InterLeukin-4 (IL-4).
For translational research in active specific ImmunoTherapy, especially in cancer, with the belief that they are essentially stimulatory or "Immunogenic."
Here we show that in vitro cultures of plastic-adherent circulating Monocytes in GM-CSF and IL-4 followed by further maturation in Interferon-gamma plus bacterial superantigens.
(DC maturing agents) can give rise to two diametrically opposite types of DCs-one stimulatory and another inhibitory.
The stimulatory DCs express higher amounts of CoStimulatory molecules, synthesize IL-12, and efficiently stimulate naive Allogeneic T-Cells in Mixed Lymphocyte Reaction (MLR).
The inhibitory DCs, in contrast, express lower concentrations of the critical CoStimulatory molecules, synthesize large amounts of IL-10, and are nonstimulatory in Allogeneic primary MLR.
Moreover, while the stimulatory DCs further amplify proliferation of T-Cells in Lectin-driven proliferation assays, the inhibitory DCs totally block T-Cell proliferation in similar assays, in vitro.
Most interestingly, neutralization of the endogenously derived IL-10 with anti-IL-10 AntiBody in DC cultures repolarizes the inhibitory DCs toward stimulatory phenotype. Accordingly, these observations have important implications in translational research involving Myeloid DCs.
Copyright 2000 Academic Press.
A subset of human Monocyte-derived Dendritic Cells expresses high levels of InterLeukin-12 in response to combined CD40+ Ligand and Interferon-γ treatment
Mosca PJ, Hobeika AC, Clay TM, Nair SK, Thomas EK, Morse MA, Lyerly HK
Blood. 2000 Nov 15;96(10):3499-504
Duke University Medical Center, Center for Genetic and Cellular Therapies, Departments of General and Thoracic Surgery, Pathology, Immunology, and Internal Medicine, Durham, NC, USA
Dendritic Cells (DCs) may arise from multiple lineages and progress through a series of intermediate stages until fully mature, at which time they are capable of optimal Antigen presentation and T-Cell activation.
High cell surface expression of CD83+ is presumed to correlate with full maturation of DCs, and a number of agents have been shown to increase CD83+ expression on DCs.
We hypothesized that InterLeukin-12 (IL-12) expression would be a more accurate marker of functionally mature DCs capable of activating Antigen-specific T-Cells.
We used combinations of signaling through CD40+, using CD40+ Ligand trimer (CD40+L), and Interferon-gamma to demonstrate that CD83+ expression is necessary but not sufficient for optimal production of IL-12 by DCs.
Phenotypically mature DCs could be induced to produce high levels of IL-12 p70 only when provided 2 simultaneous stimulatory signals.
By IntraCellular Cytokine detection, we determined that only a subset of cells that express high levels of CD80+ and CD83+ generate large amounts of IL-12.
DCs matured with both signals are superior to DCs stimulated with the individual agents in activating antigen-specific T-Cell in vitro.
These findings have important implications regarding the identification, characterization, and clinical application of functionally mature DCs.
Activity Of InterLeukin-6 In The Differentiation Of Monocytes To Macrophages And Dendritic Cells
Mitani H, Katayama N, Araki H, Ohishi K, Kobayashi K, Suzuki H, Nishii K, Masuya M, Yasukawa K, Minami N, Shiku H
Br J Haematol. 2000 May;109(2):288-95
Mie University School of Medicine, The Second Department of Internal Medicine, Tsu, Mie 514-8507, Japan
Peripheral blood Monocytes are common precursor cells of Dendritic Cells (DCs) and Macrophages. We have searched for factors with the potential to regulate the differentiation of Monocytes to DCs and Macrophages.
When CD14+ Monocytes are cultured with Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) and InterLeukin-4 (IL-4), the CD14+ CD1a- population, which consists of Macrophages, was found in the serum-containing cultures but not in the Serum-free cultures.
Addition of IL-6 receptor-neutralizing MonoClonal AntiBody (mAb) or gp130-neutralizing mAb to the Serum-containing cultures resulted in a decreased population of CD14+ CD1a- Cells.
An increase in the CD14+ CD1a- population with reduction in CD14- CD1a+ DCs was observed with the addition of IL-6 to cultures.
Whereas IL-11, Leukaemia Inhibitory Factor, Oncostatin-M or Macrophage Colony-Stimulating Factor did not affect the differentiation of Monocytes in the presence of GM-CSF plus IL-4.
This effect of IL-6 was blocked by Tumour Necrosis Factor-alpha (TNF-), LipoPolySaccharide (LPS), IL-1beta, CD40+ ligand (CD40+L) and Transforming Growth Factor beta-1 (TGF-ß-1). Among these factors, TNF- was most potent in interfering with the action of IL-6.
These results suggest that IL-6 inhibits the differentiation of Monocytes to DCs by promoting their differentiation toward Macrophages, which is modulated by factors such as TNF-, LPS, IL-1-ß, CD40+L and TGF-ß1.