Signals Required for Differentiating Dendritic Cells from Human Monocytes in Vitro

Peters, J. H.; Xu, Hui; Ostermeier, Dorothea; Friedrichs, Detlef; Gieseler, Robert K.; Ruppert, Jörg

doi:10.1007/978-1-4615-2930-9_46

Cited by 72 publications

(43 citation statements)

References 8 publications

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“…Intriguingly, high numbers of monocytes/macrophages are present in the pancreatic infiltrates of patients suffering from fulminant diabetes (33,34), which is noted for its aggressive and rapid disease progression. The pathogenic monocyte response in Tgfbr2 −/− OT-II RIP-mOva mice is in part dependent on GM-CSF, a cytokine with established roles in myeloid cell homeostasis and monocyte activation (40)(41)(42)(43). GM-CSF also promotes the development of autoimmune diseases such as arthritis and EAE (45,46,59,60), both of which are associated with pathogenic myeloid cell responses (36,37,61).…”

Section: Discussionmentioning

confidence: 99%

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Liu

Nixon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.

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Section: Discussionmentioning

confidence: 99%

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Liu

Nixon

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…The feasibility to generate human DCs from peripheral monocytes (8,9) has greatly facilitated studies on primate DC biology (10). PGE 2 , TNF, IL-1␤, and IL-6 efficiently activate immature DCs to produce IL-12p40 but not IL-12p70 (11,12).…”

Section: Il-12-impaired and Il-12-secreting Dendritic Cells Produce Imentioning

confidence: 99%

IL-12-Impaired and IL-12-Secreting Dendritic Cells Produce IL-23 upon CD154 Restimulation

Jasny

Eisenblätter

Mätz‐Rensing

et al. 2008

The Journal of Immunology

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Experimental studies in monkeys on the basis of ex vivo-generated, reinjected dendritic cells (DCs) allow investigations of primate DC biology in vivo. To study in vitro and in vivo properties of DCs with a reduced capacity to produce IL-12, we adapted findings obtained in vitro with human cells to the rhesus macaque model. Following exposure of immature monocyte-derived monkey DCs to the immunomodulating synthetic polypeptide glatiramer acetate (GA) and to dibutyryl-cAMP (d-cAMP; i.e., a cAMP enhancer that activates DCs but inhibits the induction of Th1 immune responses), the resulting DCs displayed a mature phenotype with enhanced Ag-specific T cell stimulatory function, notably also for memory Th1 cells. Phosphorylation of p38 MAPK was not induced in GA/d-cAMP-activated DCs. Accordingly, these cells secreted significantly less IL-12p40 (p ≤ 0.001) than did cytokine-activated cells. However, upon restimulation with rhesus macaque CD154, GA/d-cAMP-activated DCs produced IL-12p40/IL-23. Additionally, DCs activated by proinflammatory cytokines following protocols for the generation of cells used in clinical studies secreted significantly more IL-23 upon CD154 restimulation than following prior activation. Two days after intradermal injection, GA/d-cAMP-activated fluorescence-labeled DCs were detected in the T cell areas of draining lymph nodes. When similarly injected, GA/d-cAMP as well as cytokine-activated protein-loaded DCs induced comparable Th immune responses characterized by secretion of IFN-γ, TNF, and IL-17, and transiently expanded FOXP3+ regulatory T cells. Reactivation of primate DCs through CD154 considerably influences their immmunostimulatory properties. This may have a substantial impact on the development of innovative vaccine approaches.

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“…Cytokines and half of the medium were replaced after 3 days of culture. After a total of 7 days, nonadherent cells (Ͼ85% of the total population) were harvested and used for the subsequent experiments (15)(16)(17). To induce maturation, DCs were cultured for an additional 24 -48 h with different stimuli: 1) LPS (20 ng/ml), 2) 19 kDa lipoprotein (2 g/ml) (18), and 3) TNF-␣ alone (10 ng/ml) or in combination (maturation mix (19)) with PGE 2 (1 g/ml), IL-6 (1000 U/ml), and IL-1␤ (2 ng/ml).…”

Section: Generation Of Dcs and Macrophagesmentioning

confidence: 99%

Inverse Correlation of Maturity and Antibacterial Activity in Human Dendritic Cells

Buettner

Meinken

Bastian

et al. 2005

The Journal of Immunology

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Dendritic cells (DCs) are a key part of host defense against microbial pathogens, being part of the innate immune system, but also instructing the adaptive T cell response. This study was designed to evaluate whether human DCs directly contribute to innate immunity by killing intracellular bacteria, using tuberculosis as a model. DCs were detected in bronchoalveolar lavage samples indicating that DCs are available for immediate interaction with Mycobacterium tuberculosis (M. Tb) after inhalation of the pathogen. The phenotype of DC in bronchoalveolar lavage closely resembles monocyte-derived immature DC (iDC) according to the expression of CD1a, CD83, and CCR7. The antimicrobial activity of iDC against intracellular M. Tb inversely correlated with TNF-α-release and was enhanced by treatment with anti-TNF-α Abs. Differentiation of iDC into mature DC by addition of TNF-α or activation via Toll-like receptors further reduced killing of M. Tb. The antibacterial activity against intracellular M. Tb of all DCs was significantly lower than alveolar macrophages. Therefore, the maintenance of a pool of DCs at the site of disease activity in tuberculosis, and the maturation of these DC by TNF-α provides a mechanism by which M. Tb escapes the innate immune system.

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Signals Required for Differentiating Dendritic Cells from Human Monocytes in Vitro

Cited by 72 publications

References 8 publications

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

IL-12-Impaired and IL-12-Secreting Dendritic Cells Produce IL-23 upon CD154 Restimulation

Inverse Correlation of Maturity and Antibacterial Activity in Human Dendritic Cells

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