CD137 Ligand Signaling Research Articles

B cells in the pneumococcus-infected lung are heterogeneous and require CD4+ T cell help including CD40L to become resident memory B cells.

Recovery from respiratory pneumococcal infections generates lung-localized protection against heterotypic bacteria, mediated by resident memory lymphocytes. Optimal protection in mice requires re-exposure to pneumococcus within days of initial infection. Serial surface marker phenotyping of B cell populations in a model of pneumococcal heterotypic immunity revealed that bacterial re-exposure stimulates the immediate accumulation of dynamic and heterogeneous populations of B cells in the lung, and is essential for the establishment of lung resident memory B (BRM) cells. The B cells in the early wave were activated, proliferating locally, and associated with both CD4+ T cells and CXCL13. Antagonist- and antibody-mediated interventions were implemented during this early timeframe to demonstrate that lymphocyte recirculation, CD4+ cells, and CD40 ligand (CD40L) signaling were all needed for lung BRM cell establishment, whereas CXCL13 signaling was not. While most prominent as aggregates in the loose connective tissue of bronchovascular bundles, morphometry and live lung imaging analyses showed that lung BRM cells were equally numerous as single cells dispersed throughout the alveolar septae. We propose that CD40L signaling from antigen-stimulated CD4+ T cells in the infected lung is critical to establishment of local BRM cells, which subsequently protect the airways and parenchyma against future potential infections.

Arterial Baroreflex Dysfunction Promotes Neuroinflammation by Activating the Platelet CD40L/Nuclear Factor Kappa B Signaling Pathway in Microglia and Astrocytes

Arterial baroreflex (ABR) dysfunction has previously been associated with neuroinflammation, the most common pathological feature of neurological disorders. However, the mechanisms mediating ABR dysfunction-induced neuroinflammation are not fully understood. In the present study, we investigated the role of platelet CD40 ligand (CD40L) in neuroinflammation in an in vivo model of ABR dysfunction, and microglia and astrocyte activation in vitro. ABR dysfunction was induced in Sprague‒Dawley rats by sinoaortic denervation (SAD). We used ELSA and immunofluorescence to assess the effect of platelet CD40L on glial cell polarization and the secretion of inflammatory factors. By flow cytometry, we found that rats subjected to SAD showed a high level of platelet microaggregation and upregulation of CD40L on the platelet surface. The promotion of platelet invasion and accumulation was also observed in the brain tissues of rats subjected to SAD. In the animal model and cultured N9 microglia/C6 astrocytoma cells, platelet CD40L overexpression promoted neuroinflammation and activated M1 microglia, A1 astrocytes, and the nuclear factor kappa B (NFκB) signaling pathway. These effects were partially blocked by inhibiting platelet activity with clopidogrel or inhibiting CD40L-mediated signaling. Our results suggest that during ABR dysfunction, CD40L signaling in platelets converts microglia to the M1 phenotype and astrocytes to the A1 phenotype, activating NFκB and resulting in neuroinflammation. Thus, our study provides a novel understanding of the pathogenesis of ABR dysfunction-induced neuroinflammation and indicates that targeting platelet CD40L is beneficial for treating central nervous system (CNS) disorders associated with ABR dysfunction.

CD40L modulates transcriptional signatures of neutrophils in the bone marrow associated with development and trafficking.

Neutrophils are produced in the BM in a process called granulopoiesis, in which progenitor cells sequentially develop into mature neutrophils. During the developmental process, which is finely regulated by distinct transcription factors, neutrophils acquire the ability to exit the BM, properly distribute throughout the body, and migrate to infection sites. Previous studies have demonstrated that CD40 ligand (CD40L) influences hematopoiesis and granulopoiesis. Here, we investigate the effect of CD40L on neutrophil development and trafficking by performing functional and transcriptome analyses. We found that CD40L signaling plays an essential role in the early stages of neutrophil generation and development in the BM. Moreover, CD40L modulates transcriptional signatures, indicating that this molecule enables neutrophils to traffic throughout the body and to migrate in response to inflammatory signals. Thus, our study provides insights into the complex relationships between CD40L signaling and granulopoiesis, and it suggests a potentially novel and nonredundant role of CD40L signaling in neutrophil development and function.

SAT-070 CD137L signaling is an inflammation checkpoint in renal inflammation

We have previously shown that signaling via CD137 ligand (CD137L) promotes renal inflammation occurring after ischemia-reperfusion injury by inducing production of neutrophil-recruiting chemokines from tubular epithelial cells. In this study, we provide evidence showing that CD137L signaling enhances resolution of renal inflammation and renal tissue repair.

CD40–CD40L cross-talk drives fascin expression in dendritic cells for efficient antigen presentation to CD4+ T cells

Fascin is an actin-bundling protein that, among immune cells, is restricted to expression in dendritic cells (DCs). Previous reports have suggested that fascin plays an important role in governing DC antigen presentation to CD4+ T cells. However, no report has clearly linked the receptor-ligand engagement that can direct downstream regulation of fascin expression. In this study, bone marrow-derived DCs from wild-type versus CD40-knockout C57BL/6 mice were used to elucidate the mechanisms of fascin expression and activity upon CD40-CD40 ligand (CD40L) engagement. These investigations now show that CD40 engagement governs fascin expression in DCs to promote CD4+ T-cell cytokine production. Absence of CD40 signaling resulted in diminished fascin expression in DCs and was associated with impaired CD4+ T-cell responses. Furthermore, the study found that loss of CD40-CD40L engagement resulted in reduced DC-T-cell contacts. Rescue by ectopic fascin expression in CD40-deficient DCs was able to re-establish sustained contacts with T cells and restore cytokine production. Taken together, these results show that cross-talk through CD40-CD40L signaling drives elevated fascin expression in DCs to support acquisition of full T-cell responses.

Transcriptional and functional characterization of CD137L-dendritic cells identifies a novel dendritic cell phenotype.

The importance of monocyte-derived dendritic cells (DCs) is evidenced by the fact that they are essential for the elimination of pathogens. Although in vitro DCs can be generated by treatment of monocytes with GM-CSF and IL-4, it is unknown what stimuli induce differentiation of DCs in vivo. CD137L-DCs are human monocyte-derived DC that are generated by CD137 ligand (CD137L) signaling. We demonstrate that the gene signature of in vitro generated CD137L-DCs is most similar to those of GM-CSF and IL-4-generated immature DCs and of macrophages. This is reminiscent of in vivo inflammatory DC which also have been reported to share gene signatures with monocyte-derived DCs and macrophages. Performing direct comparison of deposited human gene expression data with a CD137L-DC dataset revealed a significant enrichment of CD137L-DC signature genes in inflammatory in vivo DCs. In addition, surface marker expression and cytokine secretion by CD137L-DCs resemble closely those of inflammatory DCs. Further, CD137L-DCs express high levels of adhesion molecules, display strong attachment, and employ the adhesion molecule ALCAM to stimulate T cell proliferation. This study characterizes the gene expression profile of CD137L-DCs, and identifies significant similarities of CD137L-DCs with in vivo inflammatory monocyte-derived DCs and macrophages.

Is CD137 Ligand (CD137L) Signaling a Fine Tuner of Immune Responses?

Now, it has been being accepted that reverse signaling through CD137 ligand (CD137L) plays an important role in vivo during hematopoiesis and in immune regulation. However, due to technical difficulty in dissecting both directional signaling events simultaneously in vivo, most biological activities caused by CD137-CD137L interactions are considered as results from signaling events of the CD137 receptor. To make the story more complex, CD137-/- and CD137L-/- mice have increased or decreased immune responses in a context-dependent manner. In this Mini review, I will try to provide a plausible explanation for how CD137L signaling is controlled during immune responses.

Regulation of Myelopoiesis by CD137L Signaling

CD137 ligand (CD137L) has emerged as a powerful regulator of myelopoiesis that links emergency situations, such as infections, to the generation of additional myeloid cells, and to their activation and maturation. CD137L is expressed on the cell surface of hematopoietic stem and progenitor cells (HSPC) and antigen presenting cells (APC) as a transmembrane protein. The signaling of CD137L into HSPC induces their proliferation and differentiation to monocytes and macrophages, and in monocytes CD137L signaling induces differentiation to potent dendritic cells (DC). CD137L signaling is initiated by CD137 which is expressed by T cells, once they become activated. Some of these activated, CD137-expressing T cells migrate from the site of infection to the bone marrow where they interact with HSPC to induce myelopoiesis, or they induce monocyte to DC differentiation locally at the site of infection. Therapeutically, induction of CD137L signaling can be utilized to reinitiate myeloid differentiation in acute myeloid leukemia cells, and to generate potent DC for immunotherapy.

CD137L-stimulated dendritic cells are more potent than conventional dendritic cells at eliciting cytotoxic T-cell responses

Dendritic cells (DCs) are highly potent initiators of adaptive immune responses and, as such, represent promising tools for immunotherapeutic applications. Despite their potential, the current efficacy of DC-based immunotherapies is poor. CD137 ligand (CD137L) signaling has been used to derive a novel type of DCs from human peripheral blood monocytes, termed CD137L-DCs. Here, we report that CD137L-DCs induce more potent cytotoxic T-cell responses than classical DCs (cDCs). Furthermore, in exploring several DC maturation factors for their ability to enhance the potency of CD137L-DCs, we found the combination of interferon γ (IFNγ) and the mixed Toll-like receptor (TLR)7/8 agonist R848, to display the highest efficacy in potentiating the T-cell co-stimulatory activity of CD137L-DCs. Of particular importance, CD137L-DCs were found to be more efficient than cDCs in activating autologous T cells targeting the cytomegalovirus (CMV)-derived protein pp65. Specifically, CD137L-DC-stimulated T cells were found to secrete higher levels of IFNγ and killed 2–3 times more HLA-matched, pp65-pulsed target cells than T cells activated by cDCs. Finally, in addition to stimulating CD8+ T cells, CD137L-DCs efficiently activated CD4+ T cells. Taken together, these findings demonstrate the superior potency of CD137L-stimulated DCs in activating CMV-specific, autologous T cells, and encourage the further development of CD137L-DCs for antitumor immunotherapy.

TLR2 Signaling in Tubular Epithelial Cells Regulates NK Cell Recruitment in Kidney Ischemia–Reperfusion Injury

Damage-associated molecular patterns released from damaged kidney cells initiate postischemic inflammation, an essential step in the progression of kidney ischemia-reperfusion injury (IRI). However, the mechanism that coordinates this highly specific process in ischemic kidneys remains to be clarified. Previously, we demonstrated that CD137 from NK cells specifically stimulates CD137 ligand (CD137L) on tubular epithelial cells (TECs) such that TECs produced the high CXCR2 chemokine levels required for neutrophil chemotaxis. We report in the present study that endogenous TLR2 ligands released from ischemic TECs induce CCR5 chemokine expression, which is critical to promoting NK cell recruitment. By implanting CD137L(-/-) TECs into the kidney capsule of TLR2(-/-) mice, we further showed that TLR2-mediated NK cell recruitment is an uncoupled event that can occur independently of CD137L signaling in TECs, which is responsible for recruiting neutrophils. Therefore, our findings identify TECs as both a target for kidney damage and also as a master regulator that actively modulates stepwise signaling, leading to the initiation and amplification of acute sterile inflammation that inflicts kidney IRI. Being clinically important, the signaling pathway of innate receptors in epithelial cells may therefore be a good target to block acute sterile inflammation resulting from tissue damage, including kidney IRI.

Role of the CD137 ligand (CD137L) signaling pathway during Mycobacterium tuberculosis infection

The role of the CD137–CD137 ligand (CD137L) signaling pathway in T cell co-stimulation has been well established. Dysregulated CD137 or CD137L stimulation can lead to pathological conditions such as inflammatory diseases or cancer. However, the contribution of CD137–CD137L interaction to the control of infectious diseases has not been extensively studied, with the few available reports focusing mainly on viral infections. Here we investigated the role of the CD137–CD137L interactions during Mycobacterium tuberculosis infection. Using CD137L-deficient mice, we found that absence of the CD137L-mediated signaling pathway during M. tuberculosis infection resulted in delayed activation of CD4+ T cells in the draining lymph nodes. This finding was supported by an in vitro mixed lymphocyte reaction assay that revealed impaired priming of T cells by CD137L-deficient dendritic cells upon mycobacterial infection. In addition, greater numbers of CD4+ T cells and antigen presenting cells were measured in the lungs of CD137L-deficient mice. Strikingly, the lung cytokine production profile was profoundly altered in M. tuberculosis-infected CD137L-deficient mice with lower levels of TNF-α, IL-12 and IL-6 and elevated concentrations of IL-17 compared to their wild type counterparts. However and surprisingly, these tangible immunological disorders translated only into a mild and transient increase in the bacterial loads and a higher number of granulomatous lesions with impaired architecture in the lungs of the CD137L-deficient infected mice. Together, while our data support the engagement of the CD137L signaling pathway during M. tuberculosis infection, they underscore the functional redundancy and robustness of the host defense arsenal deployed against mycobacterial infection.

Involvement of CD137 ligand signaling in neural stem cell death.

CD137 is a member of the tumor necrosis factor/nerve growth factor receptor superfamily. Interaction of CD137 with its ligand (CD137L) affects the apoptosis, proliferation and differentiation of immune cells. Interestingly, the CD137 receptor/ligand system involves the bi-directional transduction of signals. The expression of CD137 and its ligand is not restricted to immune organs, but can also be detected in a wide variety of tissues such as the brain, kidney, lung and heart. However, its role in brain is largely unknown. This study was performed to determine the role of CD137L reverse signaling in the apoptosis of neural stem cells. We identified the expression of CD137 and its ligand in C17.2 neural stem cells derived from mouse embryonic cerebellum. We found that the activation of CD137L reverse signaling by CD137 resulted in a decrease in cell adhesion to the fibronectin-coated culture basement, thus causing detachment-induced cell death. Furthermore, we showed that the cell death induced by CD137 was completely ameliorated by integrin activators and caspase inhibitors. Therefore we suggest that CD137L reverse signaling exerts a pro-apoptotic effect by suppressing integrin-mediated survival signals in neural stem cells.

Tumor necrosis factor receptor 1 associates with CD137 ligand and mediates its reverse signaling

Reverse signaling through CD137 ligand (CD137L) potently activates monocytes. However, the underlying mechanism is not well elucidated. This study provides evidence that tumor necrosis factor receptor 1 (TNFR1) acts as a coreceptor for CD137L and mediates CD137L signaling. CD137L colocalizes with TNFR1 on the plasma membrane and binds directly to TNFR1 via its extracellular domain. Using the human monocytic THP-1 cell line, we demonstrate that engagement of CD137L by recombinant CD137 protein promotes cell adhesion, apoptosis, expression of CD14, and production of IL-8 and tumor necrosis factor (TNF). Concomitantly, the expression of TNFR1 protein is down-regulated in response to CD137L activation, due to enhanced extracellular release and internalization of TNFR1. Activation of TNFR1 by TNF protein additively augments CD137L-induced IL-8 expression. Conversely, inhibition of TNFR1 activity by a TNFR1-neutralizing antibody inhibits CD137L-mediated cell adhesion, cell death, CD14 expression, and IL-8 production. Taken together, these data show that TNFR1 associates with CD137L and is required for CD137L reverse signaling.

CD137 ligand signaling enhances myelopoiesis during infections

CD137 and its ligand are expressed in the BM, and conflicting data exist on the regulation of myelopoiesis by the CD137 receptor-ligand system. CD137(-/-) mice have increased numbers of myeloid cells in the BM, indicating an inhibitory influence of CD137 on myelopoiesis. However, CD137 also induces proliferation of hematopoietic progenitor cells and their myeloid differentiation, arguing for an enhancing effect. Here we hypothesized that this latter case represents the situation during infections since expression of CD137 is activation dependent and strongly enhanced during inflammation. Indeed, infections with Influenza, Bordetella pertussis, Mycobacterium bovis, Bacille Calmette-Guérin or Escherichia coli or i.p. injection of LPS led to increased numbers of CD137-expressing cells, especially of CD4(+) T cells in the BM of mice. Coculture experiments confirmed that CD137 expression enables CD4(+) T cells to induce proliferation and myeloid differentiation of BM and hematopoietic progenitor cells. CD137 also enhances myelopoiesis in vivo since the infection-induced increase in myeloid cell proliferation and total myeloid cell numbers in the BM were significantly lower in CD137(-/-) mice. This study reconciles earlier conflicting data by demonstrating that while CD137-CD137L interactions inhibit myelopoiesis during steady-state conditions they increase myelopoiesis during infection.

Effect of CD40 and sCD40L on Renal Function and Survival in Patients With Renal Artery Stenosis

Activation of the CD40 receptor on the proximal tubular epithelium of the kidney results in fibrosis and inflammation in experimental models of kidney injury. Soluble CD40 ligand is released by activated platelets. The role of CD40-soluble CD40 ligand in patients with ischemic renal disease is unknown. Plasma levels of CD40 and soluble CD40 ligand were measured by enzyme-linked immunosorbent assay in a single center cohort of 60 patients with renal artery stenosis recruited from Salford Royal Hospital, Manchester, United Kingdom. A natural log transformation of CD40 and soluble CD40 ligand was performed to normalize the data. Estimated glomerular filtration rate was used as the primary indicator of renal function. By univariate analysis, low baseline levels of circulating CD40 (R(2)=0.06; P<0.05) and baseline creatinine (R(2)=0.08; P=0.022) were associated with loss of kidney function at 1-year follow-up, whereas soluble CD40 ligand was not (R(2)=0.02; P=ns). In a multiple linear regression model, CD40 (P<0.02) and baseline creatinine (P<0.01) continued to be significantly associated with a decline in renal function (model R(2)=0.17; P<0.005). Baseline CD40 levels were somewhat lower in patients who died during follow-up (survivors, 7.3±0.9 pg/mL, n=48 versus nonsurvivors, 6.7±1.0 pg/mL, n=12; P=0.06). The CD40/soluble CD40 ligand signaling cascade may be a novel mechanism contributing to the development and progression of renal injury in patients with atherosclerotic renal artery stenosis.

Inhibition or Enhancement of Proliferation of Multiple Myeloma Cell Lines by CD137 Ligand Signaling?

Abstract 4998Multiple myeloma is an plasma cell malignancy. Despite new adjuvant biotherapeutics (thalidomide-like immunomodulatory drugs and proteasome inhibitors) have improved prognosis and survival, MM is still incurable. So unraveling the intricate pathobiology and exploitation of novel therapy are needed. CD137 and its ligand are members of the Tumor Necrosis Factor (TNF) receptor and TNF superfamilies, respectively. Since CD137 ligand cross-linking enhances proliferation and survival of healthy B cells we wonder that it would also act as a growth stimulus for B cell cancers.From the study, the constitutive expression of CD137 ligand on U266, RPMI 8226, LP1, MY5 and OPM2 MM cell lines were detected as 89. 2%, 90. 9%, 57. 9%, 77. 9% and 78. 7% by Flow cytometry. Then U266 cell and RPMI 8226 cell were selected to explore the biological effect of CD137L signaling and its underlying mechanism. Resultly, in vitro study showed the proliferation and survival of U266 is enhanced by stimulating- CD137L mAb (1F1) as 4. 2*10e5 cells/ml(1F1 group) compared to 3. 5*10e5 cells/ml(control group) by cell counting at incubation for 48h. On the other wise, RPMI 8226 was not susceptible to 1F1 and was inhibited proliferation and induced cell death, by cell counting as 4. 9*10e5 cells/ml(1F1 group) compared to 5. 4*10e5 cells/ml (control group) at 48h and by CFSE as 277 compared to 197 (X-Mean of FCM) at 48h assay demonstrated. The cell cycle analysis showed that CD137 ligand induces proliferation and increases in the number of cells in the S phase from 36. 1% to 42. 5% of U266, while, showing the opposite from 50% to41% of RPMI 8226. Intracellular cytokine staining showed that treatment of cells with 1F1 increased the production of IL-6 of two cell lines, 3. 8% to 63. 9% of U266 and 90pg/ml to 250pg/ml of RPMI 8226. Finally, the two cells were treated with bortezomib and the growth of cells is analyzed by WST assay. It demonstrated that bortezomib can inhibit the function of 1F1 at U266 cells but have synergistic effection of 1F1 at RPMI 8226 cells. Inhibition rate of bortezomib were 22%, 51% and 58% of U266 and 58%, 80% and 77% of RPMI 8226 at 24h, 48h and 72h. As the inhibition rate of the two cells treated with bortezomib and 1F1 were 22. 9%, 46. 7% and 58% of U266 and 56%. 85% and 79. 7% of RPMI 8226.It is at first sight surprisingly that CD137 ligand acts in concert with 1F1 having two opposite effection in different MM cell lines. Even so, we think it needed to explain some mechanism regarding different pass ways in different cell lines(the experiment under way). Disclosures:No relevant conflicts of interest to declare.

CD137 ligand activated microglia induces oligodendrocyte apoptosis via reactive oxygen species

CD137 (4-1BB, TNFRSF9), a member of the tumor necrosis factor (TNF) receptor family, is a potent T cell co-stimulatory molecule. CD137 ligand (CD137L) is expressed by antigen presenting cells (APC) as a transmembrane protein and transmits activating signals into APC. In this study we investigated the effects of CD137L signaling in microglia, the resident APC in the central nervous system. In vitro, the murine microglia cell lines BV-2 and N9, as well as primary murine microglia responded with activation as evidenced by adherence and secretion of proinflammatory cytokines, MMP-9, and soluble intercellular adhesion molecule (ICAM). CD137L signaling is also important for microglia activation in vivo, since CD137L-deficient mice exhibited profoundly less microglia activation during experimental autoimmune encephalomyelitis (EAE) which is a well-established murine model for neuroinflammation and human multiple sclerosis (MS). Also CD137 is expressed in the CNS of mice during EAE. Activated microglia has been reported to mediate the destruction of axonal myelin sheaths and cause the death of oligodendrocytes, the main pathogenic mechanisms in EAE and MS. Corresponding to the lower microglia activation there were also fewer apoptotic oligodendrocytes in the CNS of CD137L-deficient mice. In vitro co-culture confirmed that CD137L-activated microglia induces apoptosis in oligodendrocytes, and identified reactive oxygen species as the mechanism of apoptosis induction. These data demonstrate activating effects of CD137L signaling to microglia, and show for the first time that the CD137 receptor/ligand system may be a mediator of neuroinflammatory and neurodegenerative disease, by activating microglia which in turn kill oligodendrocytes.

Species Difference of CD137 Ligand Signaling in Human and Murine Monocytes

BackgroundStimulation of CD137 ligand on human monocytes has been shown to induce DC differentiation, and these CD137L-DCs are more potent than classical DCs, in stimulating T cell responses in vitro. To allow an in vivo evaluation of the potency of CD137L-DCs in murine models we aimed at generating murine CD137L-DCs.Methodology/Principal FindingsWhen stimulated through CD137 ligand murine monocytes responded just as human monocytes with an increased adherence, morphological changes, proliferation and an increase in viable cell numbers. But CD137 ligand signaling did not induce expression of inflammatory cytokines and costimulatory molecules in murine monocytes and these cells had no T cell stimulatory activity. Murine monocytes did not differentiate to inflammatory DCs upon CD137 ligand signaling. Furthermore, while CD137 ligand signaling induces maturation of human immature classical DCs it failed to do so with murine immature classical DCs.Conclusions/SignificanceThese data demonstrate that both human and murine monocytes become activated by CD137 ligand signaling but only human and not murine monocytes differentiate to inflammatory DCs.

CD137 ligand, a member of the tumor necrosis factor family, regulates immune responses via reverse signal transduction

CD137 (4-1BB, TNFR superfamily 9) and its ligand are members of the TNFR and TNF families, respectively, and are involved in the regulation of a wide range of immune activities. CD137 ligand cross-links its receptor, CD137, which is expressed on activated T cells, and costimulates T cell activities. CD137 ligand can also be expressed as a transmembrane protein on the cell surface and transmit signals into the cells on which it is expressed (reverse signaling). CD137 ligand expression is found on most types of leukocytes and on some nonimmune cells. In monocytic cells (monocytes, macrophages, and DCs), CD137 ligand signaling induces activation, migration, survival, and differentiation. The activities of T cells, B cells, hematopoietic progenitor cells, and some malignant cells are also influenced by CD137 ligand, but the physiological significance is understood only partly. As CD137 and CD137 ligand are regarded as valuable targets for immunotherapy, it is pivotal to determine which biological effects are mediated by which of the 2 molecules.

CD137 ligand signaling induces human monocyte to dendritic cell differentiation

The ligand for CD137 (4-1BB) is expressed on peripheral human monocytes and delivers a potent activating signal via reverse signaling. Here we show that treatment of monocytes with a recombinant CD137 protein that induces reverse signaling through CD137 ligand reduces typical macrophage characteristics such as phagocytosis, oxidative burst and CD14 expression; however, typical DC characteristics including endocytosis, costimulatory molecule expression and the ability to stimulate proliferation of naïve T cells are induced. CD137-generated DC do not express DC-SIGN, CD1a or IL-12 and secrete less IL-10 than classical DC. CD137-generated DC are mature, and addition of LPS+IFN-gamma does not enhance their T-cell-stimulatory capacity. This indicates that CD137 as a sole factor is sufficient to induce development to mature DC, making stimulation of CD137 ligand the most simple protocol to generate mature DC. CD137-generated DC are more potent in inducing T-cell proliferation than classical DC. They inhibit development of Treg cells but induce T-cell expression of perforin, IFN-gamma, IL-13 and IL-17. These data demonstrate that CD137 as a single factor is sufficient to induce differentiation of peripheral monocytes to mature inflammatory DC that have a more potent T-cell-stimulatory capacity than classical DC.