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Costimulation of mast cells by 4-1BB, a member of the tumor necrosis factor receptor superfamily, with the high-affinity IgE receptor.

ABSTRACT: Mast cells are the major effector-cell type for immediate hypersensitivity and other forms of allergic reactions. Expression of 4-1BB, a member of the tumor necrosis factor receptor superfamily, is induced at mRNA and protein levels on stimulation through the high-affinity receptor for immunoglobulin E (IgE; FcepsilonRI). In this study, we present evidence that agonistic anti-4-1BB antibodies can enhance FcepsilonRI-induced cytokine production and secretion. Consistent with this, 4-1BB-deficient mast cells exhibit reduced degranulation and cytokine production on FcepsilonRI stimulation. Analysis of 4-1BB ligand (4-1BBL)-deficient cells supported this notion. As a potential mechanism for these defects, we identified a defect in Ca2+ flux induced by FcepsilonRI stimulation. The defective Ca2+ flux could be accounted for by the reduced activity of Lyn/Btk/phospholipase C-gamma2 pathway and constitutive interactions between 4-1BB and Lyn. Therefore, FcepsilonRI-inducible 4-1BB plays a costimulatory function together with FcepsilonRI stimulation.

SUBMITTER: Nishimoto H

PROVIDER: S-EPMC1416206 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Combined CD28 and 4-1BB Costimulation Potentiates Affinity-tuned Chimeric Antigen Receptor-engineered T Cells.

Project description:PURPOSE:Targeting nonspecific, tumor-associated antigens (TAA) with chimeric antigen receptors (CAR) requires specific attention to restrict possible detrimental on-target/off-tumor effects. A reduced affinity may direct CAR-engineered T (CAR-T) cells to tumor cells expressing high TAA levels while sparing low expressing normal tissues. However, decreasing the affinity of the CAR-target binding may compromise the overall antitumor effects. Here, we demonstrate the prime importance of the type of intracellular signaling on the function of low-affinity CAR-T cells. EXPERIMENTAL DESIGN:We used a series of single-chain variable fragments (scFv) with five different affinities targeting the same epitope of the multiple myeloma-associated CD38 antigen. The scFvs were incorporated in three different CAR costimulation designs and we evaluated the antitumor functionality and off-tumor toxicity of the generated CAR-T cells in vitro and in vivo. RESULTS:We show that the inferior cytotoxicity and cytokine secretion mediated by CD38 CARs of very low-affinity (K d < 1.9 × 10-6 mol/L) bearing a 4-1BB intracellular domain can be significantly improved when a CD28 costimulatory domain is used. Additional 4-1BB signaling mediated by the coexpression of 4-1BBL provided the CD28-based CD38 CAR-T cells with superior proliferative capacity, preservation of a central memory phenotype, and significantly improved in vivo antitumor function, while preserving their ability to discriminate target antigen density. CONCLUSIONS:A combinatorial costimulatory design allows the use of very low-affinity binding domains (K d < 1 ?mol/L) for the construction of safe but also optimally effective CAR-T cells. Thus, very-low-affinity scFvs empowered by selected costimulatory elements can enhance the clinical potential of TAA-targeting CARs.

| S-EPMC7477921 | biostudies-literature

CD84 negatively regulates IgE high-affinity receptor signaling in human mast cells.

Project description:CD84 is a self-binding receptor from the CD150 (or signaling lymphocyte activation molecule [SLAM]) family that is broadly expressed in hematopoietic cells. It has been described that the adaptors SLAM-associated protein (SAP) and EWS-FLI1-activated transcript 2 (EAT-2) are critical for CD150 family members' signaling and function. We observed that human mast cells express CD84 but lack SAP or EAT-2, that CD84 is tyrosine phosphorylated upon Fc?RI engagement, and that the release of granule contents is reduced when Fc?RI is coengaged with CD84 in LAD2 and human CD34(+)-derived mast cells. In addition, we observed that the release of IL-8 and GM-CSF was also reduced in Fc?RI/CD84-costimulated cells as compared with Fc?RI/Ig control. To understand how CD84 downregulates Fc?RI-mediated function, we analyzed signaling pathways affected by CD84 in human mast cells. Our results showed that CD84 dampens Fc?RI-mediated calcium mobilization after its co-cross-linking with the receptor. Furthermore, Fc?RI-mediated Syk-linker for activation of T cells-phospholipase C-?1 axis activity is downregulated after CD84 stimulation, compared with Fc?RI/Ig control. The inhibitory kinase Fes phosphorylates mainly the inhibitory motif for CD84. Moreover, Fes, which has been described to become phosphorylated after substrate binding, also gets phosphorylated when coexpressed with CD84. Consistently, Fes was observed to be more phosphorylated after CD84 and Fc?RI co-cross-linking. The phosphorylation of the protein phosphatase Src homology region 2 domain-containing phosphatase-1 also increases after CD84 and Fc?RI coengagement. Taken together, our results show that CD84 is highly expressed in mast cells and that it contributes to the regulation of Fc?RI signaling in SAP- and EAT-2-independent and Fes- and Src homology region 2 domain-containing phosphatase-1-dependent mechanisms.

| S-EPMC3233232 | biostudies-literature

Solution structure of the cysteine-rich domain in Fn14, a member of the tumor necrosis factor receptor superfamily.

Project description:Fn14 is the smallest member of the tumor necrosis factor (TNF) receptor superfamily, and specifically binds to its ligand, TWEAK (TNF-like weak inducer of apoptosis), which is a member of the TNF superfamily. The receptor-ligand recognition between Fn14 and TWEAK induces a variety of cellular processes for tissue remodeling and is also involved in the pathogenesis of some human diseases, such as cancer, chronic autoimmune diseases, and acute ischaemic stroke. The extracellular ligand-binding region of Fn14 is composed of 53 amino acid residues and forms a single, cysteine-rich domain (CRD). In this study, we determined the solution structure of the Fn14 CRD (Glu28-Ala70) by heteronuclear NMR, with a (13)C-/(15)N-labeled sample. The tertiary structure of the CRD comprises a beta-sheet with two strands, followed by a 3(10) helix and a C-terminal alpha-helix, and is stabilized by three disulfide bonds connecting Cys36-Cys49, Cys52-Cys67, and Cys55-Cys64. Comparison of the disulfide bond connectivities and the tertiary structures with those of other CRDs revealed that the Fn14 CRD is similar to the fourth CRD of TNF receptor 1 (A1-C2 module type), but not to the CRD of B-cell maturation antigen and the second CRD of transmembrane activator and CAML (calcium modulator and cyclophilin ligand) interactor (A1-D2 module type). This is the first structural report about the A1-C2 type CRD that could bind to the known target.

| S-EPMC2760370 | biostudies-literature

Lysophosphatidic Acid Triggers Apoptosis in HeLa Cells through the Upregulation of Tumor Necrosis Factor Receptor Superfamily Member 21.

Project description:Lysophosphatidic acid (LPA), a naturally occurring bioactive phospholipid, activates G protein-coupled receptors (GPCRs), leading to regulation of diverse cellular events including cell survival and apoptosis. Despite extensive studies of the signaling pathways that mediate LPA-regulated cell growth and survival, the mechanisms underlying the apoptotic effect of LPA remain largely unclear. In this study, we investigated this issue in HeLa cells. Our data demonstrate that LPA induces apoptosis in HeLa cells at pathologic concentrations with a concomitant upregulation of the expression of TNFRSF21 (tumor necrosis factor receptor superfamily member 21), also known as death receptor number 6 (DR6) involved in inflammation. Moreover, treatment of cells with LPA receptor (LPAR) antagonist abolished the DR6 upregulation by LPA. LPA-induced DR6 expression was also abrogated by pertussis toxin (PTX), an inhibitor of GPCRs, and by inhibitors of PI3K, PKC, MEK, and ERK. Intriguingly, LPA-induced DR6 expression was specifically blocked by dominant-negative form of PKCδ (PKCδ-DN). LPA-induced DR6 expression was also dramatically inhibited by knockdown of ERK or CREB. These results suggest that activation of the MEK/ERK pathway and the transcription factor CREB mediate LPA-induced DR6 expression. More interestingly, knockdown of DR6 using siRNA approach remarkably attenuated LPA-induced apoptosis. In conclusion, our results suggest that LPA-induced apoptosis in HeLa cells is mediated by the upregulation of DR6 expression.

| S-EPMC5350427 | biostudies-literature

Costimulation via the tumor-necrosis factor receptor superfamily couples TCR signal strength to the thymic differentiation of regulatory T cells.

Project description:Regulatory T cells (Treg cells) express members of the tumor-necrosis factor (TNF) receptor superfamily (TNFRSF), but the role of those receptors in the thymic development of Treg cells is undefined. We found here that Treg cell progenitors had high expression of the TNFRSF members GITR, OX40 and TNFR2. Expression of those receptors correlated directly with the signal strength of the T cell antigen receptor (TCR) and required the coreceptor CD28 and the kinase TAK1. The neutralization of ligands that are members of the TNF superfamily (TNFSF) diminished the development of Treg cells. Conversely, TNFRSF agonists enhanced the differentiation of Treg cell progenitors by augmenting responsiveness of the interleukin 2 receptor (IL-2R) and transcription factor STAT5. Costimulation with the ligand of GITR elicited dose-dependent enrichment for cells of lower TCR affinity in the Treg cell repertoire. In vivo, combined inhibition of GITR, OX40 and TNFR2 abrogated the development of Treg cells. Thus, expression of members of the TNFRSF on Treg cell progenitors translated strong TCR signals into molecular parameters that specifically promoted the development of Treg cells and shaped the Treg cell repertoire.

| S-EPMC4000541 | biostudies-other

Mast Cells Exhibiting Strong Cytoplasmic Staining for IgE and High Affinity IgE Receptor are Increased in IgG4-Related Disease.

Project description:Immunoglobulin G4 (IgG4)-related disease is characterized by elevated serum IgG4 levels and increased numbers of IgG4-positive cells. However, its pathogenesis is not fully understood. We previously suggested that mast cells may play an important role in IgG4-related disease. In this study, we confirmed the characteristics of mast cells in IgG4-related lymphadenopathy by using immunohistochemistry and dual immunofluorescence. We analyzed 23 cases of IgG4-related lymphadenopathy and compared them with 23 cases of non-specific lymphoid hyperplasia. The majority of patients with IgG4-related lymphadenopathy had cervical lesions with involvement of other organs. Immunohistologically, mast cells with strong cytoplasmic staining for immunoglobulin E and high affinity immunoglobulin E receptor were significantly increased in IgG4-related lymphadenopathy as compared to those in non-specific lymphoid hyperplasia (mean: 3.83?±?3.99 cells per high power field and 7.14?±?8.21 cells per high power field, respectively; P?=?0.007 and P?=?0.011). In addition, dual immunofluorescence assay showed that immunoglobulin E and high affinity immunoglobulin E receptor staining exhibited a cytoplasmic granular pattern in IgG4-related lymphadenopathy, suggesting internalization of the antibodies and receptors. Our findings showed that mast cell activation might be involved in the pathogenesis of IgG4-related disease.

| S-EPMC5854596 | biostudies-literature

Impact of TNF receptor superfamily member costimulation on the transcriptome of in vitro CD3/CD28 activated mouse Tregs

Project description:Activated Foxp3+ regulatory T cells (Tregs) express several TNF receptor superfamily (TNFRSF) members. Here, we analyzed the transcriptome of purified Tregs that were activated with anti-CD3 and anti-CD28 mAbs, IL-2 and with or without agonists of TNFR2, 4-1BB, DR3 and OX40 for 18h and 36h. Triggering these TNFRSF in Tregs induces similar changes in gene expression patterns, suggesting that they engage common signal transduction pathways. Among them, we identified a major role of canonical NF-κB.

2020-04-01 | GSE146135 | GEO

Rab25 Small GTPase Mediates Secretion of Tumor Necrosis Factor Receptor Superfamily Member 11b (osteoprotegerin) Protecting Cancer Cells from Effects of TRAIL.

Project description:BACKGROUND:Expression of Rab25, which is located in the 1q amplicon present at high frequency in many cancer lineages, promotes cancer cell survival under multiple stress conditions. While Rab proteins play essential roles in all stages of vesicle trafficking, the functions and endogenous cargoes for Rab25 remain to be fully elucidated. Osteoprotegerin (OPG) is a secreted glycoprotein that binds the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) thus preventing it from activating the TNF-family death receptors. In the present study, we demonstrated that Rab25 regulates OPG at both the transcription and secretion level. METHODS:The effect of Rab25 on OPG expression and its effect on TRAIL-induced cell were examined in both ovarian and breast cells. Signal transduction pathways regulation of OPG expression was examined in cells using pharmacogenetic approaches. RESULTS:Expression of Rab25 to levels similar to those in tumors with RAB25 amplification, increased OPG mRNA expression and secretion from ovarian and breast cancer cell lines, whereas down regulation with Rab25 specific siRNA decreased OPG secretion and sensitized cells to TRAIL-induced cell death. Critically, exogenous OPG mimicked the effects of Rab25 on cell death supporting the contention that Rab25-induced accumulation of OPG protects cancer cells from the effects of TRAIL. Rab25 cooperates with EGFR-mediated MAPK signaling to increase TRAIL production and release. Importantly, priming cells with EGFR inhibitors increased sensitivity to TRAIL-induced cells death regardless of the Rab25 background. CONCLUSION:Increased OPG expression induced by Rab25 may provide a mechanistic advantage for cancer development and progression.

| S-EPMC4266180 | biostudies-literature

Targeting of the tumor necrosis factor receptor superfamily for cancer immunotherapy.

Project description:The tumor necrosis factor (TNF) ligand and cognate TNF receptor superfamilies constitute an important regulatory axis that is pivotal for immune homeostasis and correct execution of immune responses. TNF ligands and receptors are involved in diverse biological processes ranging from the selective induction of cell death in potentially dangerous and superfluous cells to providing costimulatory signals that help mount an effective immune response. This diverse and important regulatory role in immunity has sparked great interest in the development of TNFL/TNFR-targeted cancer immunotherapeutics. In this review, I will discuss the biology of the most prominent proapoptotic and co-stimulatory TNF ligands and review their current status in cancer immunotherapy.

| S-EPMC3693168 | biostudies-literature

The structure of the trimer of human 4-1BB ligand is unique among members of the tumor necrosis factor superfamily.

Project description:Binding of the 4-1BB ligand (4-1BBL) to its receptor, 4-1BB, provides the T lymphocyte with co-stimulatory signals for survival, proliferation, and differentiation. Importantly, the 4-1BB-4-1BBL pathway is a well known target for anti-cancer immunotherapy. Here we present the 2.3-A crystal structure of the extracellular domain of human 4-1BBL. The ectodomain forms a homotrimer with an extended, three-bladed propeller structure that differs from trimers formed by other members of the tumor necrosis factor (TNF) superfamily. Based on the 4-1BBL structure, we modeled its complex with 4-1BB, which was consistent with images obtained by electron microscopy, and verified the binding site by site-directed mutagenesis. This structural information will facilitate the development of immunotherapeutics targeting 4-1BB.

| S-EPMC2838339 | biostudies-literature

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