Death receptor 3 signaling enhances proliferation of human regulatory T cells

Bittner, Sebastian; Knoll, Gertrud; Ehrenschwender, Martin

doi:10.1002/1873-3468.12632

Cited by 14 publications

(14 citation statements)

References 47 publications

(85 reference statements)

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“…It is established that TL1A/DR3 signalling results in a generalised, non-specific stimulation of all major T cell effector pathways, for example, Th1, Th2 and Th17, which have been shown to play a pivotal role in the pathogenesis of psoriasis 18–21. In addition, recent reports suggested that DR3 signalling might also play a functional role in human T regulatory cells 22. In this study, we showed that the percentage of DR3+ PBMCs was significantly elevated in PBMCs from patients with PV compared with those from patients with AD and the control healthy volunteers.…”

Section: Discussionsupporting

confidence: 56%

Expression of death receptor 3 (DR3) on peripheral blood mononuclear cells of patients with psoriasis vulgaris

Lin

et al. 2018

Postgraduate Medical Journal

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BackgroundA series of previous reports indicated that tumour necrosis factor-like ligand 1A (TL1A) and its receptor death receptor 3 (DR3) are involved in the pathogenesis of psoriasis vulgaris (PV), which is a common chronic skin disease accompanied by a number of comorbidities, although their exact roles remain unclear. Our previous studies demonstrated that serum TL1A levels were substantially elevated in patients with PV, but the detection of DR3 expression in peripheral blood mononuclear cells (PBMCs) of patients with PV had not been reported. Therefore, we detected DR3 expression on CD4+, CD8+, CD14+ and CD19+ PBMCs of patients with PV, atopic dermatitis (AD) and healthy volunteers.MethodsBlood samples were collected from participants with PV before and after treatment. Then, PBMCs from patients with PV were isolated. The Psoriasis Area Severity Index (PASI) was used to assess severity in patients with PV. The DR3 on CD4+, CD8+, CD14+ and CD19+ PBMCs were detected by flow cytometry analysis. Pearson’s correlation analysis was then used to investigate the relationship between DR3 expression and PASI scores in patients with PV.ResultsComparing with the healthy volunteers and patients with AD, the percentage of DR3-expressing on CD8+ and CD14+ PBMCs in patients with PV was elevated, but the percentage of DR3-expressing on CD8+ and CD14+ cells decreased after anti-inflammatory treatment, which was correlated with PASI scores.ConclusionsTaken together, these findings suggest that DR3 may play a key role in the pathogenesis of PV.

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Section: Discussionsupporting

confidence: 56%

Expression of death receptor 3 (DR3) on peripheral blood mononuclear cells of patients with psoriasis vulgaris

Lin

et al. 2018

Postgraduate Medical Journal

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“…For predicting the percentage of Tregs in human metastatic melanoma, the LASSO regression model selected interactions involving the TNFRSF25 receptor expressed on Tregs and its ligand TNFRSF15 expressed by T helper (Th) cells as well as an interaction between PSEN1 expressed by B cells and the NOTCH2 receptor expressed on Tregs. Previous studies have shown that decreases in Notch2 expression can reduce the proportion of Tregs, whereas agonist antibodies targeting the TNFRSF25 receptor can help expand Treg populations (Bittner et al, 2017;Qin et al, 2017;Schreiber et al, 2010). Altogether, these results suggest that our approach of linking cell-cell interactions to phenotypes of interest has the potential to identify biologically relevant interactions.…”

Section: Discussionmentioning

confidence: 72%

Analysis of Single-Cell RNA-Seq Identifies Cell-Cell Communication Associated with Tumor Characteristics

et al. 2018

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Graphical AbstractHighlights d Ligand-receptor interactions in tumors were investigated using single-cell RNA-seq d Identified interactions were regressed against phenotypic measurements of tumors d The approach provides a tool for studying cell-cell interactions and their variability In BriefTumors are composed of cancer cells and many non-malignant cell types, such as immune and stromal cells. To better understand how all cell types in a tumor cooperate to facilitate malignant growth, Kumar et al. studied communication between cells via ligand and receptor interactions using single-cell data and computational modeling. SUMMARYTumor ecosystems are composed of multiple cell types that communicate by ligand-receptor interactions. Targeting ligand-receptor interactions (for instance, with immune checkpoint inhibitors) can provide significant benefits for patients. However, our knowledge of which interactions occur in a tumor and how these interactions affect outcome is still limited. We present an approach to characterize communication by ligand-receptor interactions across all cell types in a microenvironment using single-cell RNA sequencing. We apply this approach to identify and compare the ligand-receptor interactions present in six syngeneic mouse tumor models. To identify interactions potentially associated with outcome, we regress interactions against phenotypic measurements of tumor growth rate. In addition, we quantify ligand-receptor interactions between T cell subsets and their relation to immune infiltration using a publicly available human melanoma dataset. Overall, this approach provides a tool for studying cell-cell interactions, their variability across tumors, and their relationship to outcome.We thank Merrimack Pharmaceuticals, Inc. for sponsoring the research and supporting publication of the results and the internal review team for reviewing the article prior to submission. We also acknowledge the NIGMS Interdisciplinary Biotechnology Training Program (T32-GM008334) and NCI (U01-CA215798) for funding (to M.P.K. and D.A.L.). K. performed all computational analyses. J.D. and Y.J. processed the mouse syngeneic tumor samples, performed the flow cytometry analysis, and obtained the scRNA-seq data. A.S. provided the tumor growth data. M.P.K., A.R., and G.L. helped design the computational analysis. D.C.

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“…For human Tregs, however, neither expression nor a potential function of DR3 have until recently been investigated. Our lab proved DR3 expression on isolated human Tregs and showed TL1A‐induced activation of MAPKs and the NFκB pathway . Furthermore, addition of TL1A during in vitro expansion increased the yield of human Treg while their suppressive capacity was retained.…”

Section: Dr3 Signaling In Immune Cellsmentioning

confidence: 80%

“…In contrast to the ubiquitous expression of its close relative TNFR1, DR3 expression is more restricted and has been reported for innate lymphoid cells (ILCs) [5][6][7], CD4+ [8][9][10][11][12] and CD8+ T cells [8,13,14], tissueresident memory T cells [15] and B cells [16,17]. Notably, T-or B-cell receptor activation can upregulate DR3 expression.…”

mentioning

confidence: 99%

Multifaceted death receptor 3 signaling—promoting survival and triggering death

Bittner

Ehrenschwender

2017

FEBS Letters

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Death Receptor 3 (DR3) and its cognate ligand TL1A belong to the tumor necrosis factor superfamily (TNFSF). This sophisticated network of receptor-ligand systems controls innumerable biological processes. For many (if not all) TNFSF ligands and receptors, a role in conditions such as inflammation, tissue development, proliferation, and cell death has been firmly established. However, relatively little is known about DR3 and TL1A. Here, we review novel aspects of DR3 signaling and DR3-associated signaling pathways before summarizing the function of DR3 in the immune system. The emerging role of DR3 in disease will be addressed before we finally critically discuss the potential therapeutic exploitation of this receptor-ligand pair.

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Death receptor 3 signaling enhances proliferation of human regulatory T cells

Cited by 14 publications

References 47 publications

Expression of death receptor 3 (DR3) on peripheral blood mononuclear cells of patients with psoriasis vulgaris

Expression of death receptor 3 (DR3) on peripheral blood mononuclear cells of patients with psoriasis vulgaris

Analysis of Single-Cell RNA-Seq Identifies Cell-Cell Communication Associated with Tumor Characteristics

Multifaceted death receptor 3 signaling—promoting survival and triggering death

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