scholarly journals Role of syndecan-1 in the interaction between dendritic cells and T cells

2020 ◽  
Author(s):  
M Kouwenberg ◽  
A Rops ◽  
M Bakker-van Bebber ◽  
L Diepeveen ◽  
M Götte ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mixed Lymphocyte Reaction ◽  
Cell Interaction ◽  
Allograft Survival ◽  
Stimulatory Capacity ◽  
Transplant Model ◽  
Cell Stimulatory Capacity

AbstractSyndecan-1 (Sdc-1) is a heparan sulfate proteoglycan that can bind cytokines and chemokines via its heparan sulfate side chains, and has immunomodulatory properties in experimental models. Sdc-1 expression has been reported on dendritic cells (DC) and T cells. The potential role of Sdc-1 in DC - T cell interaction has not been investigated yet. We postulate that Sdc-1 is involved in DC – T cell interaction and may influence graft survival in an allogeneic transplant model.Sdc-1 expression on bone marrow-derived DC and T cells was analyzed by flow cytometry. Unstimulated and LPS stimulated Sdc-1 deficient DC were evaluated in vitro for phenotype and stimulatory capacity in mixed lymphocyte reaction. Sdc-1 deficient T cells were evaluated for proliferative capacity and differentiation in a mixed lymphocyte reaction and a proliferation assay. Allograft survival was evaluated in a fully MHC mismatched heterotopic heart transplant model, with either Sdc-1 deficient donors or recipients.Sdc-1 is expressed on the cell surface of unstimulated and LPS matured DC. Sdc-1 deficiency had no effect on expression of co-stimulatory molecules, cytokine production or T cell stimulatory capacity as compared to WT DC. Sdc-1 expression was not detectable on WT T cells, although intracellular Sdc-1 expression could be demonstrated after ConA activation. Sdc-1 deficient T cells showed reduced proliferation upon DC or ConA stimulation and reduced IL-17 production upon ConA stimulation, compared to WT T cells. Sdc-1 deficiency of either allograft or recipient did not prolong allograft survival.In conclusion, Sdc-1 is expressed on the cell surface of DC, where its absence does not affect DC phenotype or T cell stimulatory capacity. Sdc-1 is intracellularly expressed in ConA activated T cells. Sdc-1 deficiency in T cells results in a reduced proliferative response in vitro, as induced by DC and ConA. Sdc-1 deficiency in donor or recipient does not affect allograft survival.

scholarly journals Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo.

1996 ◽  
Vol 184 (4) ◽  
pp. 1413-1424 ◽  
Author(s):  
T De Smedt ◽  
B Pajak ◽  
E Muraille ◽  
L Lespagnard ◽  
E Heinen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Marginal Zone ◽  
White Pulp ◽  
Bacterial Product ◽  
Stimulatory Capacity ◽  
Lps Treatment ◽  
Cell Stimulatory Capacity

Dendritic cells (DC) are described as "nature's adjuvant," since they have the capacity to sensitize T cells in vivo upon first encounter with the antigen. The potent accessory properties of DC appear to develop sequentially. In particular, the ability to process antigens and to sensitize native T cells develops in sequence, a process termed "maturation" that is well described in vitro. Here, we obtain evidence for maturation in vivo in response to the bacterial product lipopolysaccharide (LPS). Before LPS treatment, many DC are found at the margin between the red and white pulp. These cells lack the M342 and DEC-205 markers, but process soluble proteins effectively. 6 h after LPS, DC with the M342 and DEC-205 markers are found in increased numbers in the T cell areas. These cells have a reduced capacity to process proteins, but show increases in the B7 costimulator and T cell stimulatory capacity. 48 h after LPS, the number of DC in the spleen is reduced markedly. We interpret these findings to mean that LPS can cause DC in the marginal zone to mature and to migrate into and then out of the T cell areas.

scholarly journals Siplizumab, an Anti-CD2 Monoclonal Antibody, Induces a Unique Set of Immune Modulatory Effects Compared to Alemtuzumab and Rabbit Anti-Thymocyte Globulin In Vitro

2020 ◽  
Vol 11 ◽  
Author(s):  
Christian Binder ◽  
Felix Sellberg ◽  
Filip Cvetkovski ◽  
Erik Berglund ◽  
David Berglund
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mixed Lymphocyte Reaction ◽  
T Cell Proliferation ◽  
Allogeneic Mixed Lymphocyte Reaction ◽  
Dependent Cell

Antibodies are commonly used in organ transplant induction therapy and to treat autoimmune disorders. The effects of some biologics on the human immune system remain incompletely characterized and a deeper understanding of their mechanisms of action may provide useful insights for their clinical application. The goal of this study was to contrast the mechanistic properties of siplizumab with Alemtuzumab and rabbit Anti-Thymocyte Globulin (rATG). Mechanistic assay systems investigating antibody-dependent cell-mediated cytotoxicity, antibody-dependent cell phagocytosis and complement-dependent cytotoxicity were used to characterize siplizumab. Further, functional effects of siplizumab, Alemtuzumab, and rATG were investigated in allogeneic mixed lymphocyte reaction. Changes in T cell activation, T cell proliferation and frequency of naïve T cells, memory T cells and regulatory T cells induced by siplizumab, Alemtuzumab and rATG in allogeneic mixed lymphocyte reaction were assessed via flow cytometry. Siplizumab depleted T cells, decreased T cell activation, inhibited T cell proliferation and enriched naïve and bona fide regulatory T cells. Neither Alemtuzumab nor rATG induced the same combination of functional effects. The results presented in this study should be used for further in vitro and in vivo investigations that guide the clinical use of immune modulatory biologics.

scholarly journals Transmigration across a Steady-State Blood–Brain Barrie Induces Activation of Circulating Dendritic Cells Partly Mediated by Actin Cytoskeletal Reorganization

Membranes ◽  
2021 ◽  
Vol 11 (9) ◽  
pp. 700
Author(s):  
Megha Meena ◽  
Mats Van Delen ◽  
Maxime De Laere ◽  
Ann Sterkens ◽  
Coloma Costas Romero ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Dendritic Cells ◽  
Steady State ◽  
T Cell ◽  
Cytoskeletal Reorganization ◽  
Blood Brain ◽  
Stimulatory Capacity ◽  
The Central Nervous System ◽  
Cell Stimulatory Capacity

The central nervous system (CNS) is considered to be an immunologically unique site, in large part given its extensive protection by the blood–brain barrier (BBB). As our knowledge of the complex interaction between the peripheral immune system and the CNS expands, the mechanisms of immune privilege are being refined. Here, we studied the interaction of dendritic cells (DCs) with the BBB in steady–state conditions and observed that transmigrated DCs display an activated phenotype and stronger T cell-stimulatory capacity as compared to non-migrating DCs. Next, we aimed to gain further insights in the processes underlying activation of DCs following transmigration across the BBB. We investigated the interaction of DCs with endothelial cells as well as the involvement of actin cytoskeletal reorganization. Whereas we were not able to demonstrate that DCs engulf membrane fragments from fluorescently labelled endothelial cells during transmigration across the BBB, we found that blocking actin restructuring of DCs by latrunculin-A significantly impaired in vitro migration of DC across the BBB and subsequent T cell-stimulatory capacity, albeit no effect on migration-induced phenotypic activation could be demonstrated. These observations contribute to the current understanding of the interaction between DCs and the BBB, ultimately leading to the design of targeted therapies capable to inhibit autoimmune inflammation of the CNS.

scholarly journals Endogenous dendritic cells mediate the effects of intravenously injected therapeutic immunosuppressive dendritic cells in transplantation

Blood ◽  
2010 ◽  
Vol 116 (15) ◽  
pp. 2694-2705 ◽  
Author(s):  
Sherrie J. Divito ◽  
Zhiliang Wang ◽  
William J. Shufesky ◽  
Quan Liu ◽  
Olga A. Tkacheva ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Indirect Pathway ◽  
Allograft Survival ◽  
Complex Molecules ◽  
Cell Responses ◽  
Histocompatibility Complex

Abstract The prevailing idea regarding the mechanism(s) by which therapeutic immunosuppressive dendritic cells (DCs) restrain alloimmunity is based on the concept that they interact directly with antidonor T cells, inducing anergy, deletion, and/or regulation. However, this idea has not been tested in vivo. Using prototypic in vitro–generated maturation-resistant (MR) DCs, we demonstrate that once MR-DCs carrying donor antigen (Ag) are administered intravenously, they decrease the direct and indirect pathway T-cell responses and prolong heart allograft survival but fail to directly regulate T cells in vivo. Rather, injected MR-DCs are short-lived and reprocessed by recipient DCs for presentation to indirect pathway CD4+ T cells, resulting in abortive activation and deletion without detrimental effect on the number of indirect CD4+ FoxP3+ T cells, thus increasing the regulatory to effector T cell relative percentage. The effect on the antidonor response was independent of the method used to generate therapeutic DCs or their viability; and in accordance with the idea that recipient Ag-presenting cells mediate the effects of therapeutic DCs in transplantation, prolongation of allograft survival was achieved using donor apoptotic MR-DCs or those lacking surface major histocompatibility complex molecules. We therefore conclude that therapeutic DCs function as Ag-transporting cells rather than Ag-presenting cells to prolong allograft survival.

Upregulation of Osteoactivin Upon Exposure to Tyrosine Kinase Inhibitors Impairs the T Cell Stimulatory Capacity of Monocyte-Derived Dendritic Cells

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1112-1112
Author(s):  
Michael Gutknecht ◽  
Lisa Güttler ◽  
Mark-Alexander Schwarzbich ◽  
Julia Salih ◽  
Lothar Kanz ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Cancer Patients ◽  
Transmembrane Glycoprotein ◽  
Stimulatory Capacity ◽  
Ifn Γ ◽  
Tki Treatment ◽  
Cell Stimulatory Capacity

Abstract Abstract 1112 Targeted therapies using tyrosine kinase (TK) inhibitors have significantly improved the treatment of cancer patients. Imatinib (Glivec, Gleevec, STI 571) was the first TK inhibitor (TKI) established for the treatment of cancer and efficiently blocks the activity of c-ABL, a non-receptor TK which is pathologically activated in philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia (CML). Nilotinib (Tasigna) and dasatinib (Sprycel) are second-generation TKI that have shown efficacy in the treatment of Ph+ CML resistant or intolerant to imatinib. However, molecularly detectable disease persists in the majority of patients treated with TKI, causing relapse after discontinuation of TKI treatment in many cases. Thus, multiple approaches presently aim to combine TKI treatment with immunotherapy. As TKI, besides targeting their eponymous enzyme, influence multiple other signaling pathways involved in cellular functions, analysis of potential effects of TKI on immune effector cells may be key to develop successful combinatorial strategies. Due to their unique ability to initiate powerful anti-tumor T cell responses, dendritic cells (DC) are employed in many immunotherapeutic strategies aiming to eradicate the malignant cell population. Upon activation they change their expression pattern of cell surface molecules and secreted cytokines/chemokines, a process called DC maturation. Osteoactivin, also known as transmembrane glycoprotein NMB (GPNMB) and dendritic cell-associated transmembrane protein (DC-HIL), is a type I transmembrane glycoprotein that is detected abundantly in DC but not or substantially less in monocytes. Its expression can inhibit T cell activation by binding the type 1 transmembrane proteoglycan syndecan-4 (SD-4) on T cells. Here we extend our findings that the exposure of human peripheral blood monocytes to the immunosuppressive and anti-inflammatory cytokine IL-10 or to therapeutic concentrations of TKI during differentiation into monocyte-derived DC (moDC) leads to significant upregulation of osteoactivin at the transcript and protein level in vitro (Blood 2010 116: abstract 1733). We analyzed the expression of other inhibitory receptors, such as PD-L1, PD-L2, CD80, or CD86 and observed no significant differences of the expression under TKI treatment. Furthermore, we thoroughly examined the expression of osteoactivin in the presence of relevant maturation signals such as TLR ligands, IFN-γ or TNF. LPS, Poly I:C, Pam3Cys or R848 nearly abolished osteoactivin expression compared to untreated control cells. In contrast, IFN-γ or TNF did not significantly reduce osteoactivin expression below the basal level. To evaluate the involvement of osteoactivin in TKI-triggered effects on moDC function we performed mixed lymphocyte reactions with allogenic T cells. Osteoactivin upregulation upon exposure to imatinib, dasatinib and nilotinib resulted in significantly reduced T cell stimulatory capacity of moDC. This was not due to IL-10 upregulation but rather due to direct inhibitory effects of osteoactivin on T cell proliferation which could be overcome by addition of blocking anti-osteoactivin antibody. Our data demonstrate that upregulation of osteoactivin upon exposure of immature moDC to TKI is critically involved in the inhibition of DC function. These findings indicate that inhibition of osteoactivin expression or function may serve as a novel strategy in combinatory approaches using TKI and DC-based immunotherapy and may enhance the efficacy of immunotherapeutic interventions in cancer patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals IL-27 promotes T cell–dependent colitis through multiple mechanisms

2010 ◽  
Vol 208 (1) ◽  
pp. 115-123 ◽  
Author(s):  
Jennifer H. Cox ◽  
Noelyn M. Kljavin ◽  
Nandhini Ramamoorthi ◽  
Lauri Diehl ◽  
Marcel Batten ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Inflammation ◽  
Interferon Γ ◽  
Transfer Model ◽  
Proinflammatory Role ◽  
Immune Pathology

Interleukin-27 (IL-27) is a cytokine known to have both proinflammatory and immunoregulatory functions. The latter appear to dominate in vivo, where IL-27 suppresses TH17 responses and promotes the differentiation of Tr1 cells expressing interferon-γ and IL-10 and lacking forkhead box P3 (Foxp3). Accordingly, IL-27 receptor α (Il27ra)–deficient mice suffer from exacerbated immune pathology when infected with various parasites or challenged with autoantigens. Because the role of IL-27 in human and experimental mouse colitis is controversial, we studied the consequences of Il27ra deletion in the mouse T cell transfer model of colitis and unexpectedly discovered a proinflammatory role of IL-27. Absence of Il27ra on transferred T cells resulted in diminished weight loss and reduced colonic inflammation. A greater fraction of transferred T cells assumed a Foxp3+ phenotype in the absence of Il27ra, suggesting that IL-27 functions to restrain regulatory T cell (Treg) development. Indeed, IL-27 suppressed Foxp3 induction in vitro and in an ovalbumin-dependent tolerization model in vivo. Furthermore, effector cell proliferation and IFN-γ production were reduced in the absence of Il27ra. Collectively, we describe a proinflammatory role of IL-27 in T cell–dependent intestinal inflammation and provide a rationale for targeting this cytokine in pathological situations that result from a breakdown in peripheral immune tolerance.

scholarly journals Role of Protein Kinase C and Nox2-Derived Reactive Oxygen Species Formation in the Activation and Maturation of Dendritic Cells by Phorbol Ester and Lipopolysaccharide

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Judith Stein ◽  
Sebastian Steven ◽  
Matthias Bros ◽  
Stephan Sudowe ◽  
Michael Hausding ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Dendritic Cells ◽  
Protein Kinase C ◽  
T Cell ◽  
Oxygen Species ◽  
Kinase C ◽  
Stimulatory Capacity ◽  
Ros Formation ◽  
Cell Stimulatory Capacity

Aims. Activation/maturation of dendritic cells (DCs) plays a central role in adaptive immune responses by antigen processing and (cross-) activation of T cells. There is ongoing discussion on the role of reactive oxygen species (ROS) in these processes and with the present study we investigated this enigmatic pathway.Methods and Results. DCs were cultured from precursors in the bone marrow of mice (BM-DCs) and analyzed for ROS formation, maturation, and T cell stimulatory capacity upon stimulation with phorbol ester (PDBu) and lipopolysaccharide (LPS). LPS stimulation of BM-DCs caused maturation with moderate intracellular ROS formation, whereas PDBu treatment resulted in maturation with significant ROS formation. The NADPH oxidase inhibitors apocynin/VAS2870 and genetic gp91phox deletion both decreased the ROS signal in PDBu-stimulated BM-DCs without affecting maturation and T cell stimulatory capacity of BM-DCs. In contrast, the protein kinase C inhibitors chelerythrine/Gö6983 decreased PDBu-stimulated ROS formation in BM-DCs as well as maturation.Conclusion. Obviously Nox2-dependent ROS formation in BM-DCs is not always required for their maturation or T cell stimulatory potential. PDBu/LPS-triggered BM-DC maturation rather relies on phosphorylation cascades. Our results question the role of oxidative stress as an essential “danger signal” for BM-DC activation, although we cannot exclude contribution by other ROS sources.

scholarly journals CELL INTERACTIONS IN THE IMMUNE RESPONSE IN VITRO

1972 ◽  
Vol 136 (4) ◽  
pp. 737-760 ◽  
Author(s):  
Marc Feldmann
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Cell Interaction ◽  
T And B Lymphocytes ◽  
Activated T Cells ◽  
Cell Cooperation

The mechanism of interaction of T and B lymphocytes was investigated in an in vitro hapten carrier system using culture chambers with two compartments separated by a cell impermeable nucleopore membrane. Because specific cell interaction occurred efficiently across this membrane, contact of T and B lymphocytes was not essential for cooperation which must have been mediated by a subcellular component or "factor." By using different lymphoid cell populations in the lower culture chamber and activated thymus cells in the upper chamber (with antigen present in both), it was found that the antigen-specific mediator acted indirectly on B cells, through the agency of macrophages. Macrophages which had been cultured in the presence of activated T cells and antigen acquired the capacity to specifically induce antibody responses in B cell-containing lymphoid populations. Trypsinization of these macrophages inhibited their capacity to induce immune responses, indicating that the mediator of cell cooperation is membrane bound. By using antisera to both the haptenic and carrier determinants of the antigen as blocking reagents, it was demonstrated that the whole antigen molecule was present on the surface of macrophages which had been exposed to activated T cells and antigen. Because specifically activated T cells were essential a component of the antigen-specific mediator must be derived from these cells. By using anti-immunoglobulin sera as inhibitors of the binding of the mediator to macrophages, the T cell component was indeed found to contain both κ- and µ-chains and was thus presumably a T cell-derived immunoglobulin. It was proposed that cell cooperation is mediated by complexes of T cell IgM and antigen, bound to the surface of macrophage-like cells, forming a lattice of appropriately spaced antigenic determinants. B cells become immunized by interacting with this surface. With this mechanism of cell cooperation, the actual pattern of antigen-B cell receptor interactions in immunization would be the same with both thymus-dependent and independent antigens. An essential feature of the proposed mechanism of cell cooperation is that macrophage-B cell interaction must occur at an early stage of the antibody response, a concept which is supported by many lines of evidence. Furthermore this mechanism of cell interaction can be elaborated to explain certain phenomena such as the highly immunogenic macrophage-bound antigen, antigenic competition, the distinction between immunity and tolerance in B lymphocytes, and the possible mediation of tolerance by T lymphocytes.

scholarly journals Bacterial Pathogens Induce Abscess Formation by CD4+ T-Cell Activation via the CD28–B7-2 Costimulatory Pathway

2000 ◽  
Vol 68 (12) ◽  
pp. 6650-6655 ◽  
Author(s):  
Arthur O. Tzianabos ◽  
Anil Chandraker ◽  
Wiltrud Kalka-Moll ◽  
Francesca Stingele ◽  
Victor M. Dong ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Pathogenic Bacteria ◽  
Cell Activation ◽  
Bacterial Pathogens ◽  
Abscess Formation

ABSTRACT Abscesses are a classic host response to infection by many pathogenic bacteria. The immunopathogenesis of this tissue response to infection has not been fully elucidated. Previous studies have suggested that T cells are involved in the pathologic process, but the role of these cells remains unclear. To delineate the mechanism by which T cells mediate abscess formation associated with intra-abdominal sepsis, the role of T-cell activation and the contribution of antigen-presenting cells via CD28-B7 costimulation were investigated. T cells activated in vitro by zwitterionic bacterial polysaccharides (Zps) known to induce abscess formation required CD28-B7 costimulation and, when adoptively transferred to the peritoneal cavity of naı̈ve rats, promoted abscess formation. Blockade of T-cell activation via the CD28-B7 pathway in animals with CTLA4Ig prevented abscess formation following challenge with different bacterial pathogens, including Staphylococcus aureus,Bacteroides fragilis, and a combination ofEnterococcus faecium and Bacteroides distasonis. In contrast, these animals had an increased abscess rate following in vivo T-cell activation via CD28 signaling. Abscess formation in vivo and T-cell activation in vitro required costimulation by B7-2 but not B7-1. These results demonstrate that abscess formation by pathogenic bacteria is under the control of a common effector mechanism that requires T-cell activation via the CD28–B7-2 pathway.

scholarly journals Small Molecule Cyclotriazadisulfonamide Abrogates the Upregulation of the Human Receptors CD4 and 4-1BB and Suppresses In Vitro Activation and Proliferation of T Lymphocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Elisa Claeys ◽  
Eva Pauwels ◽  
Stephanie Humblet-Baron ◽  
Becky Provinciael ◽  
Dominique Schols ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Small Molecule ◽  
T Cell Activation ◽  
Cell Activation ◽  
Mixed Lymphocyte Reaction ◽  
Protein Biosynthesis ◽  
Cell Subpopulation ◽  
Survival Factor

The small molecule cyclotriazadisulfonamide (CADA) down-modulates the human CD4 receptor, an important factor in T cell activation. Here, we addressed the immunosuppressive potential of CADA using different activation models. CADA inhibited lymphocyte proliferation with low cellular toxicity in a mixed lymphocyte reaction, and when human PBMCs were stimulated with CD3/CD28 beads, phytohemagglutinin or anti-CD3 antibodies. The immunosuppressive effect of CADA involved both CD4+ and CD8+ T cells but was, surprisingly, most prominent in the CD8+ T cell subpopulation where it inhibited cell-mediated lympholysis. Immunosuppression by CADA was characterized by suppressed secretion of various cytokines, and reduced CD25, phosphoSTAT5 and CTPS-1 levels. We discovered a direct down-modulatory effect of CADA on 4-1BB (CD137) expression, a survival factor for activated CD8+ T cells. More specifically, CADA blocked 4‑1BB protein biosynthesis by inhibition of its co-translational translocation into the ER in a signal peptide-dependent way. Taken together, this study demonstrates that CADA, as potent down-modulator of human CD4 and 4‑1BB receptor, has promising immunomodulatory characteristics. This would open up new avenues toward chemotherapeutics that act as selective protein down-modulators to treat various human immunological disorders.

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