scholarly journals Induction of antigen-specific regulatory T lymphocytes by human dendritic cells expressing the glucocorticoid-induced leucine zipper

Blood ◽  
2007 ◽  
Vol 110 (1) ◽  
pp. 211-219 ◽  
Author(s):  
Haifa Hamdi ◽  
Véronique Godot ◽  
Marie-Christine Maillot ◽  
Maria Victoria Prejean ◽  
Nicolas Cohen ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocytes ◽  
Antigen Presentation ◽  
Leucine Zipper ◽  
Ex Vivo ◽  
Antigen Presenting Cells ◽  
Interleukin 10 ◽  
Therapeutic Effects ◽  
Regulatory T Lymphocytes ◽  
Antigen Presenting

Dendritic cells (DCs) determine whether antigen presentation leads to immune activation or to tolerance. Tolerance-inducing DCs (also called regulatory DCs) act partly by generating regulatory T lymphocytes (Tregs). The mechanism used by DCs to switch toward regulatory DCs during their differentiation is unclear. We show here that human DCs treated in vitro with glucocorticoids produce the glucocorticoid-induced leucine zipper (GILZ). Antigen presentation by GILZ-expressing DCs generates CD25highFOXP3+CTLA-4/CD152+ and interleukin-10–producing Tregs inhibiting the response of CD4+ and CD8+ T lymphocytes. This inhibition is specific to the antigen presented, and only proliferating CD4+ T lymphocytes express the Treg markers. Interleukin-10 is required for Treg induction by GILZ-expressing DCs. It is also needed for the suppressive function of Tregs. Antigen-presenting cells from patients treated with glucocorticoids generate interleukin-10–secreting Tregs ex vivo. These antigen-presenting cells produce GILZ, which is needed for Treg induction. Therefore, GILZ is critical for commitment of DCs to differentiate into regulatory DCs and to the generation of antigen-specific Tregs. This mechanism may contribute to the therapeutic effects of glucocorticoids.

scholarly journals Sensitization by intratracheally injected dendritic cells is independent of antigen presentation by host antigen-presenting cells

2008 ◽  
Vol 85 (1) ◽  
pp. 64-70 ◽  
Author(s):  
H. Kuipers ◽  
T. Soullie ◽  
H. Hammad ◽  
M. Willart ◽  
M. Kool ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Antigen Presentation ◽  
Antigen Presenting Cells ◽  
Antigen Presenting

FTY720 (fingolimod) treatment tips the balance towards less immunogenic antigen-presenting cells in patients with multiple sclerosis

2015 ◽  
Vol 21 (14) ◽  
pp. 1811-1822 ◽  
Author(s):  
Felix Luessi ◽  
Stefan Kraus ◽  
Bettina Trinschek ◽  
Steffen Lerch ◽  
Robert Ploen ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Dendritic Cells ◽  
Healthy Subjects ◽  
Ex Vivo ◽  
Antigen Presenting Cells ◽  
Direct Effects ◽  
Quantitative Analyses ◽  
Ifn Γ ◽  
Multiple Sclerosis Patients ◽  
Antigen Presenting

Objective: We aimed to clarify whether fingolimod has direct effects on antigen-presenting cells in multiple sclerosis patients. Methods: Frequency and phenotype of directly ex vivo dendritic cells and monocytes were analyzed in 43 individuals, including fingolimod-treated and untreated multiple sclerosis patients as well as healthy subjects. These cells were further stimulated with lipopolysaccharide to determine functional effects of fingolimod treatment. Results: Absolute numbers of CD1c+ dendritic cells and monocytes were not significantly reduced in fingolimod-treated patients indicating that fingolimod did not block the migration of antigen-presenting cells to peripheral blood. CD86 was upregulated on CD1c+ dendritic cells and thus their activation was not impaired under fingolimod treatment. Quantitative analyses of gene transcription in cells and protein content in supernatants from ex vivo CD1c+ dendritic cells and monocytes, however, showed lower secretion of TNFα, IL1-β and IL-6 upon lipopolysaccharide-stimulation. These results could be matched with CD4+MOG-specific transgenic T cells exhibiting reduced levels of TNFα and IFN-γ but not IL-4 upon stimulation with murine dendritic cells loaded with MOG, when treated with fingolimod. Conclusions: Our data indicate that fingolimod – apart from trapping lymphocytes in lymph nodes – exerts its disease-modulating activity by rebalancing the immune tolerance networks by modulation of antigen-presenting cells.

GILZ expression in human dendritic cells redirects their maturation and prevents antigen-specific T lymphocyte response

Blood ◽  
2006 ◽  
Vol 107 (5) ◽  
pp. 2037-2044 ◽  
Author(s):  
Nicolas Cohen ◽  
Enguerran Mouly ◽  
Haifa Hamdi ◽  
Marie-Christine Maillot ◽  
Marc Pallardy ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Leucine Zipper ◽  
Transforming Growth Factor ◽  
Cd40 Ligand ◽  
Dc Functions ◽  
Circulating Antigen ◽  
Lymphocyte Responses ◽  
Antigen Presenting

Interleukin (IL)-10 and glucocorticoids (GCs) inhibit the ability of antigen-presenting dendritic cells (DCs) to stimulate T lymphocytes. We show that induction of GILZ (GC-induced leucine zipper) is involved in this phenomenon. IL-10, dexamethasone (DEX), and transforming growth factor (TGF)β stimulate GILZ production in human immature DCs derived from monocytes and from CD34+ cells. GILZ is necessary and sufficient for DEX, IL-10, and TGFβ modulation of CD80, CD83, CD86, immunoglobulin-like transcript (ILT)-3, and B7-H1 expression by DCs, and alteration of DC functions. GILZ stimulates the production of IL-10 by immature DCs and prevents the production of inflammatory chemokines by CD40L-activated DCs. In contrast, GILZ does not prevent CD40 ligand-mediated inhibition of phagocytosis, indicating that it affects some but not all aspects of DC maturation. GILZ prevents DCs from activating antigen-specific T lymphocyte responses. Administration of GCs to patients stimulates GILZ expression in their circulating antigen-presenting cells, and this contributes to the weak lymphocyte responses of GC-treated patients. Thus, regulation of GILZ expression is an important factor determining the decision of DCs whether or not to stimulate T lymphocytes, and IL-10, GCs, and TGFβ share this mechanism for influencing DC functions and the balance between immune response and tolerance.

scholarly journals Regulatory Macrophages and Tolerogenic Dendritic Cells in Myeloid Regulatory Cell-Based Therapies

2021 ◽  
Vol 22 (15) ◽  
pp. 7970
Author(s):  
Maaike Suuring ◽  
Aurélie Moreau
Keyword(s):  
Dendritic Cells ◽  
Organ Transplantation ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Myeloid Cell ◽  
Interleukin 10 ◽  
Regulatory Cell ◽  
Cell Based Therapy ◽  
Antigen Presenting

Myeloid regulatory cell-based therapy has been shown to be a promising cell-based medicinal approach in organ transplantation and for the treatment of autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, Crohn’s disease and multiple sclerosis. Dendritic cells (DCs) are the most efficient antigen-presenting cells and can naturally acquire tolerogenic properties through a variety of differentiation signals and stimuli. Several subtypes of DCs have been generated using additional agents, including vitamin D3, rapamycin and dexamethasone, or immunosuppressive cytokines, such as interleukin-10 (IL-10) and transforming growth factor-beta (TGF-β). These cells have been extensively studied in animals and humans to develop clinical-grade tolerogenic (tol)DCs. Regulatory macrophages (Mregs) are another type of protective myeloid cell that provide a tolerogenic environment, and have mainly been studied within the context of research on organ transplantation. This review aims to thoroughly describe the ex vivo generation of tolDCs and Mregs, their mechanism of action, as well as their therapeutic application and assessment in human clinical trials.

scholarly journals Uptake of HLA Alloantigens via CD89 and CD206 Does Not Enhance Antigen Presentation by Indirect Allorecognition

2016 ◽  
Vol 2016 ◽  
pp. 1-12 ◽  
Author(s):  
Eytan Breman ◽  
Jurjen M. Ruben ◽  
Kees L. Franken ◽  
Mirjam H. M. Heemskerk ◽  
Dave L. Roelen ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Antigen Presentation ◽  
Antigen Presenting Cells ◽  
Mannose Receptor ◽  
Class Ii ◽  
Hla Class Ii ◽  
Indirect Allorecognition ◽  
Antigen Presenting

In organ transplantation, alloantigens are taken up by antigen presenting cells and presented via the indirect pathway to T-cells which in turn can induce allograft rejection. Monitoring of these T-cells is of major importance; however no reliable assay is available to routinely monitor indirect allorecognition. Recently we showed that HLA monomers can be successfully used to monitor indirect allorecognition. Targeting antigens to endocytic receptors on antigen presenting cells may further enhance the presentation of antigens via HLA class II and improve the efficiency of this assay. In the current study we explored targeting of HLA monomers to either CD89 expressing monocytes or mannose receptor expressing dendritic cells. Monomer-antibody complexes were generated using biotin-labeled monomers and avidin labeling of the antibodies. We demonstrate that targeting the complexes to these receptors resulted in a dose-dependent HLA class II mediated presentation to a T-cell clone. The immune-complexes were efficiently taken up and presented to T-cells. However, the level of T-cell reactivity was similar to that when only exogenous antigen was added. We conclude that HLA-A2 monomers targeted for presentation through CD89 on monocytes or mannose receptor on dendritic cells lead to proper antigen presentation but do not enhance indirect allorecognition via HLA-DR.

The restrictive role of sialic acid in antigen presentation to a subset of human peripheral cd4+ t lymphocytes that requires antigen-presenting dendritic cells

1989 ◽  
Vol 19 (10) ◽  
pp. 1829-1834 ◽  
Author(s):  
Martien L. Kapsenberg ◽  
Frank E. M. Stiekema ◽  
Aram Kallan ◽  
Jan D. Bos ◽  
Robert C. Roozemond
Keyword(s):  
Dendritic Cells ◽  
Sialic Acid ◽  
T Lymphocytes ◽  
Antigen Presentation ◽  
Antigen Presenting

scholarly journals Inhibition of CD1 Antigen Presentation by Human Cytomegalovirus

2008 ◽  
Vol 82 (9) ◽  
pp. 4308-4319 ◽  
Author(s):  
Martin J. Raftery ◽  
Manuel Hitzler ◽  
Florian Winau ◽  
Thomas Giese ◽  
Bodo Plachter ◽  
...  
Keyword(s):  
Immune Response ◽  
Antigen Presentation ◽  
Human Cytomegalovirus ◽  
Antigen Presenting Cells ◽  
Interleukin 10 ◽  
Antiviral Immune Response ◽  
Simplex Virus ◽  
Antigen Presenting ◽  
Group 1

ABSTRACT The betaherpesvirus human cytomegalovirus (HCMV) encodes several molecules that block antigen presentation by the major histocompatibility complex (MHC) proteins. Humans also possess one other family of antigen-presenting molecules, the CD1 family; however, the effect of HCMV on CD1 expression is unknown. The majority of CD1 molecules are classified on the basis of homology as group 1 CD1 and are present almost exclusively on professional antigen-presenting cells such as dendritic cells, which are a major target for HCMV infection and latency. We have determined that HCMV encodes multiple blocking strategies targeting group 1 CD1 molecules. CD1 transcription is strongly inhibited by the HCMV interleukin-10 homologue cmvIL-10. HCMV also blocks CD1 antigen presentation posttranscriptionally by the inhibition of CD1 localization to the cell surface. This function is not performed by a known HCMV MHC class I-blocking molecule and is substantially stronger than the blockage induced by herpes simplex virus type 1. Antigen presentation by CD1 is important for the development of the antiviral immune response and the generation of mature antigen-presenting cells. HCMV present in antigen-presenting cells thus blunts the immune response by the blockage of CD1 molecules.

Hsp90 Is Critical for the Regulation of Phenotype and Functionality of Human Dendritic Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2401-2401
Author(s):  
Jooeun Bae ◽  
Constantine Mitsiades ◽  
Tai Yu-Tzu ◽  
Jeff Martinson ◽  
Ramesh Babu Batchu ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Immune System ◽  
T Lymphocytes ◽  
Clinical Data ◽  
Antigen Presenting Cells ◽  
Hsp90 Inhibitor ◽  
Antigen Uptake ◽  
Dc Function ◽  
Antigen Presenting ◽  
Inhibitor Treatment

Abstract Hsp90, a molecular chaperone, plays a critical role in protein folding and transport, and thereby it modulates cellular activity. Pre-clinical data shows over-expression of Hsp90 in multiple myeloma (MM) and efficacy of Hsp90 inhibitor in myeloma has been determined in vitro. Based on these results, phase I/II trial evaluating clinical efficacy of the Hsp90 inhibitor is underway in MM. Although Hsp90 inhibitor shows significant effects on tumor cells, there is limited information concerning its effects on the immune system. The objective of this study was to evaluate the effects of Geldanamycin on activity of antigen-presenting cells. Immature and mature monocyte derived dendritic cells (DC) from normal human donors were used as the source of antigen-presenting cells in this study. Geldanamycin treatment of DC for 24 hours had no effect on cell viability (>90%), however, it led to a significant down-regulation of surface antigens associated with activation (CD86, CD80), maturation (CD83) and antigen presentation (HLA-ABC, HLA-DPQR). This decline was associated with changes in gene expression levels of these antigens, however the protein expression analyzed by % positive cells was not down-regulated with the treatment. Exposure to Hsp90 inhibitor was associated with significant decreases in IL-12 secretion (untrt vs. trt = 135 vs. 21 pg/ml), antigen uptake (MFI untrt 798 vs. MFI trt 449, Dextran-FITC), and antigen processing. These changes were associated with decline in DC function, which were demonstrated by significant decrease in Hsp90-treated DC compared to untreated DC in presentation of Tetanus Toxoid to autologous T lymphocytes (untrt vs. trt = 73 % vs. 47 %, CFSE proliferation), allogeneic T lymphocytes stimulation (untrt vs. trt = 232795 cpm vs. 116876 cpm, 3H-thymidine incorporation), and induction of IFN-g secretion from allogenic T lymphocytes (untrt vs. trt = 500 vs. 30 pg/ml). Taken together, these results show significant decline in DC function following Hsp90 inhibitor treatment. Further studies are underway using MM patient samples pre- and post-Hsp90 inhibitor treatment to understand in vivo effects on the immune system. Our pre-clinical data suggests the need to consider proper sequence of various therapeutic modalities, including immunotherapy, to optimize and improve clinical outcome.

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