CD137 ligand interacts with CD32a to trigger reverse CD137 ligand signaling.
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ABSTRACT:
SUBMITTER: Zeng Q
PROVIDER: S-EPMC7784954 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:CD137 is a costimulatory molecule expressed on activated T cells. Its ligand, CD137L, is expressed on the surface of hematopoietic progenitor cells, and upon binding to CD137 induces reverse signaling into hematopoietic progenitor cells promoting their activation, proliferation and myeloid differentiation. Since aging is associated with an increasing number of myeloid cells we investigated the role of CD137 and CD137L on myelopoiesis during aging. Comparing 3 and 12 months old WT, CD137?/? and CD137L?/? mice we found significantly more granulocytes and monocytes in the bone marrow of older WT mice, while this age?dependent increase was absent in CD137?/? and CD137L?/? mice. Instead, the bone marrow of 12 months old CD137?/? and CD137L?/? mice was characterized by an accumulation of hematopoietic progenitor cells, suggesting that the differentiation of hematopoietic progenitor cells became arrested in the absence of CD137L signaling. CD137L signaling is initiated by activated CD137?expressing, CD4+ T cells. These data identify a novel molecular mechanisms underlying immune aging by demonstrating that CD137?expressing CD4+ T cells in the bone marrow engage CD137L on hematopoietic progenitor cells, and that this CD137L signaling biases hematopoiesis towards myelopoiesis during aging.
| S-EPMC3808697 | biostudies-literature
Project description:The contribution of monocyte-derived dendritic cells (DC) to an immune response is essential for the elimination of pathogens. In vitro DC can be generated by treatment of monocytes with GM-CSF + IL-4 but it is unknown what stimuli induce the differentiation of monocytes to DC in vivo. CD137L-DC are human monocyte-derived DC that are generated by CD137 ligand (CD137L) signaling. Since CD137 is only expressed at sites of inflammation it would be a suitable signal for the induction of monocyte-derived DC. Here we report on gene expression analysis of CD137L-DC, immature and mature classical DC, monocytes and macrophages which indicates that CD137L-DC have a gene signature that is most similar to that of classical DC. Additionally, CD137L-DC signature genes are highly enriched in monocyte-derived DC which were isolated from sites of inflammation. Also cell surface marker expression and cytokine secretion of CD137L-DC are highly similar to that of inflammatory monocyte-derived DC. CD137L-DC express high levels of adhesion molecules, display strong attachment and employ the adhesion molecule ALCAM to stimulate T cell proliferation. This study identifies a physiological stimulus for the generation of monocyte-derived DC in vivo. A total of 30 expression profiles were obtained, on 6 APC subtypes from 5 different donors
2016-06-30 | E-GEOD-60199 | biostudies-arrayexpress
Project description:The contribution of monocyte-derived dendritic cells (DC) to an immune response is essential for the elimination of pathogens. In vitro DC can be generated by treatment of monocytes with GM-CSF + IL-4 but it is unknown what stimuli induce the differentiation of monocytes to DC in vivo. CD137L-DC are human monocyte-derived DC that are generated by CD137 ligand (CD137L) signaling. Since CD137 is only expressed at sites of inflammation it would be a suitable signal for the induction of monocyte-derived DC. Here we report on gene expression analysis of CD137L-DC, immature and mature classical DC, monocytes and macrophages which indicates that CD137L-DC have a gene signature that is most similar to that of classical DC. Additionally, CD137L-DC signature genes are highly enriched in monocyte-derived DC which were isolated from sites of inflammation. Also cell surface marker expression and cytokine secretion of CD137L-DC are highly similar to that of inflammatory monocyte-derived DC. CD137L-DC express high levels of adhesion molecules, display strong attachment and employ the adhesion molecule ALCAM to stimulate T cell proliferation. This study identifies a physiological stimulus for the generation of monocyte-derived DC in vivo.
2016-06-30 | GSE60199 | GEO
Project description:CD137 is a costimulatory molecule expressed on activated T cells. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC), which use the CD137-CD137L system to enhance immune responses. It was, therefore, surprising to discover CD137 expression on regulatory T cells (Treg). The function of CD137 in Treg are controversial. While some studies report that CD137 signalling converts Treg to effector T cells (Teff), other studies find that CD137-expressing Treg display a stronger inhibitory activity than CD137- Treg. Here, we describe that CD137 on Treg binds to CD137L on APC, upon which one of the two molecules is transferred via trogocytosis to the other cell, where CD137-CD137L forms a complex that is internalized and deprives APC of the immune-stimulatory CD137L. Truncated forms of CD137 that lack the cytoplasmic domain of CD137 are also able to downregulate CD137L, demonstrating that CD137 signalling is not required. Comparable data have been obtained with human and murine cells, indicating that this mechanism is evolutionarily conserved. These data describe trogocytosis of CD137 and CD137L as a new mechanism employed by Treg to control immune responses by downregulating the immunostimulatory CD137L on APC.
| S-EPMC7914903 | biostudies-literature
Project description:The potent costimulatory effect of CD137 has been implicated in several murine autoimmune disease models. CD137 costimulates and polarizes antigen-specific T cells toward a potent Th1/Tc1 response, and is essential for the development of experimental autoimmune encephalomyelitis (EAE), a murine model of Multiple Sclerosis (MS). This study aimed to investigate a role of CD137 in MS. Immunohistochemical and immunofluorescence staining of MS brain tissues was used to identify expression of CD137. CD137+ cells were identified in MS brain samples, with active lesions having the highest frequency of CD137+ cells. CD137 expression was found on several leukocyte subsets, including T cells, B cells and endothelial cells. In particular, CD137+ B cells were found in meningeal infiltrates. In vitro experiments showed that CD137 engagement on activated B cells increased early TNF and persistent IL-6 secretion with increased cell proliferation. These CD137+ B cells could interact with CD137L-expressing cells, secrete pro-inflammatory cytokines and accumulate in the meningeal infiltrate. This study demonstrates CD137 expression by activated B cells, enhancement of the inflammatory activity of B cells upon CD137 engagement, and provides evidence for a pathogenic role of CD137+ B cells in MS.
| S-EPMC7677239 | biostudies-literature
Project description:One major challenge in the development of cancer therapeutics is the selective delivery of the drugs to their cellular targets. In the case of pancreatic cancer, the ?-2 receptor is a unique target that triggers apoptosis upon activation. We have previously developed a series of chemical compounds with high affinity for the ?-2 receptor and showed rapid internalization of the ligands. One particular specific ligand of the ?-2 receptor, SV119, binds to pancreatic cancer cells and induces target cell death in vitro and in vivo. In this study, we characterized the ability of SV119 to selectively deliver other death-inducing cargos to augment the cytotoxic properties of SV119 itself. When conjugated to SV119, small molecules that are known to interfere with intracellular prosurvival pathways retained their ability to induce cell death, the efficiency of which was enhanced by the combinatorial effect of SV119 delivered with its small molecule cargo. Our findings define a simple platform technology to increase the tumor-selective delivery of small molecule therapeutics via ?-2 ligands, permitting chemotherapeutic synergy that can optimize efficacy and patient benefit.
| S-EPMC3251632 | biostudies-literature
Project description:Rationale: Reverse triggering is an underexplored form of dyssynchrony with important clinical implications in patients with acute respiratory distress syndrome.Objectives: This retrospective study identified reverse trigger phenotypes and characterized their impacts on Vt and transpulmonary pressure.Methods: Fifty-five patients with acute respiratory distress syndrome on pressure-regulated ventilator modes were included. Four phenotypes of reverse triggering with and without breath stacking and their impact on lung inflation and deflation were investigated.Measurements and Main Results: Inflation volumes, respiratory muscle pressure generation, and transpulmonary pressures were determined and phenotypes differentiated using Campbell diagrams of respiratory activity. Reverse triggering was detected in 25 patients, 15 with associated breath stacking, and 13 with stable reverse triggering consistent with respiratory entrainment. Phenotypes were associated with variable levels of inspiratory effort (mean 4-10 cm H2O per phenotype). Early reverse triggering with early expiratory relaxation increased Vts (88 [64-113] ml) and inspiratory transpulmonary pressures (3 [2-3] cm H2O) compared with passive breaths. Early reverse triggering with delayed expiratory relaxation increased Vts (128 [86-170] ml) and increased inspiratory and mean-expiratory transpulmonary pressure (7 [5-9] cm H2O and 5 [4-6] cm H2O). Mid-cycle reverse triggering (initiation during inflation and maximal effort during deflation) increased Vt (51 [38-64] ml), increased inspiratory and mean-expiratory transpulmonary pressure (3 [2-4] cm H2O and 3 [2-3] cm H2O), and caused incomplete exhalation. Late reverse triggering (occurring exclusively during exhalation) increased mean expiratory transpulmonary pressure (2 [1-2] cm H2O) and caused incomplete exhalation. Breath stacking resulted in large delivered volumes (176 [155-197] ml).Conclusions: Reverse triggering causes variable physiological effects, depending on the phenotype. Differentiation of phenotype effects may be important to understand the clinical impacts of these events.
| S-EPMC7781129 | biostudies-literature
Project description:Treatment of Caco-2-BBe intestinal epithelial cells (BBe) with TNF-α and lymphotoxin-β (LT-β) receptor agonists induced the expression of the TNF receptor superfamily gene TNFRSF9/CD137. In the gut, these cytokines are known to be involved in both inflammatory responses and development of organized lymphoid tissues; thus, it was notable that in CD137-deficient mice Peyer's patch M cells lacked transcytosis function. To examine the direct effect of CD137 expression on epithelial cell function independent of other cytokine effects including CD137L triggering, we stably transfected BBe cells to express CD137. CD137 was found at the cell surface as well as the cytoplasm, and confocal microscopy suggested that aggregates of CD137 at the lateral and basolateral surface may be associated with cytoplasmic actin filament termini. Many of the CD137 clusters were colocalized with extracellular fibronectin providing a possible alternative ligand for CD137. Interestingly, we found that CD137-expressing cells showed significantly higher transepithelial electrical resistance (TEER) accompanied by an increase in claudin-4 and decrease in claudin-3 protein expression. By contrast, transfection with a truncated CD137 lacking the cytoplasmic signaling domain did not affect TEER. Finally, CD137-deficient mice showed increased intestinal permeability upon dextran sodium sulfate (DSS) treatment as compared to control mice. Our results suggest that cytokine-induced expression of CD137 may be important in enhancing epithelial barrier function in the presence of intestinal inflammation as well as influencing cytoskeletal organization.
| S-EPMC4246582 | biostudies-literature
Project description:The CD137-CD137 ligand (CD137L) costimulatory system is a critical immune checkpoint with pathophysiological implications in autoimmunity. In this study, we investigated the role of CD137L-mediated costimulation on renal, cutaneous and cerebral manifestations in lupus and the underlying immunological mechanism. Lupus-prone C57BL/6lpr-/- (B6.lpr) mice were crossed to C57BL/6.CD137L-/- mice to obtain CD137L-deficient B6.lpr [double knock out (DKO)] mice. We investigated the extent of survival, glomerulonephritis, skin lesions, cerebral demyelination, immune deviation and long-term synaptic plasticity among the two mouse groups. Cytokine levels, frequency of splenic leukocyte subsets and phenotypes were compared between DKO, B6.lpr and B6.WT mice. A 22 month observation of 226 DKO and 137 B6.lpr mice demonstrated significantly more frequent proliferative glomerulonephritis, larger skin lesions and shorter survival in DKO than in B6.lpr mice. Conversely, microglial activation and cerebral demyelination were less pronounced while long-term synaptic plasticity, was superior in DKO mice. Splenic Th17 cells were significantly higher in DKO than in B6.lpr and B6.WT mice while Th1 and Th2 cell frequencies were comparable between DKO and B6.lpr mice. IL-10 and IL-17 expression by T cells was not affected but there were fewer IL-10-producing myeloid (CD11b+) cells, and also lower serum IL-10 levels in DKO than in B6.lpr mice. The absence of CD137L causes an immune deviation toward Th17, fewer IL-10-producing CD11b+ cells and reduced serum IL-10 levels which potentially explain the more severe lupus in DKO mice while leading to reduced microglia activation, lesser cerebral damage and less severe neurological deficits.
| S-EPMC6607944 | biostudies-literature
Project description:TRAF2 dependent K63-polyubiquitinations have been recently shown to connect CD137 (4-1BB) stimulation to NF-κB activation. In a search of deubiquitinase enzymes (DUBs) that could regulate such a signaling route, A20 and CYLD were found to coimmunoprecipitate with CD137 and TRAF2 complexes. Indeed, overexpression of A20 or CYLD downregulated CD137-elicited ubiquitination of TRAF2 and TAK1 upon stimulation with agonist monoclonal antibodies. Moreover, overexpression of A20 or CYLD downregulated CD137-induced NF-κB activation in cultured cells and in gene-transferred hepatocytes in vivo, while silencing these deubiquitinases enhanced CD137 costimulation of primary human CD8 T cells. Therefore A20 and CYLD directly downregulate the signaling from a T and NK-cell costimulatory receptor under exploitation for cancer immunotherapy in clinical trials.
| S-EPMC5739564 | biostudies-literature