Detection of Experimental and Clinical Immune Complexes by Measuring SHIP-1 Recruitment to the Inhibitory FcγRIIB

Stopforth, Richard J.; Oldham, Robert J.; Tutt, Alison L.; Duriez, Patrick J.; Chan, H T Claude; Binkowski, Brock F.; Zimprich, Chad; Li, Dun; Hargreaves, Philip G.; Cong, Mei; Reddy, Venkat; Leandro, Maria; Cambridge, G; Lux, Anja; Nimmerjahn, Falk; Cragg, Mark S.

doi:10.4049/jimmunol.1700832

Cited by 8 publications

(7 citation statements)

References 57 publications

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“…SHIP-1 is associated with the negative regulation of T cell activation [ 21 ]. Early experiments have shown that the engagement of CD3 or CD28 on T cells leads to the phosphorylation and catalytic activation of SHIP-1, indicating a role for SHIP-1 in lymphocyte activation [ 22 ]. Silencing SHIP-1 in CD4 + T lymphocytes leads to a decrease in the level of the p-ERK protein and reduces the proliferation and motility of CD4 + T cells [ 23 ].…”

Section: Resultsmentioning

confidence: 99%

“…TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. TIGIT was first identified as an inhibitory receptor that exerts immunosuppressive effects through activated CD4 + T cells, Tregs and NK cells [ 10 , 21 , 22 ]. Studies examining the immunosuppressive effect of TIGIT on CD8 + T cells are increasing.…”

Section: Discussionmentioning

confidence: 99%

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Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer

et al. 2022

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Objective TIGIT/CD155 has attracted widespread attention as a new immune checkpoint and a potential target for cancer immunotherapy. In our study, we evaluated the role of TIGIT/CD155 checkpoints in the progression of cervical cancer. Methods The expression of CD155 and TIGIT in cervical cancer tissues was detected using flow cytometry, immunohistochemistry (IHC) and gene expression profiling. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8+ T cells to produce cytokines. Changes in the NF-κB and ERK pathways were detected using western blotting (WB) after blocking TIGIT/CD155 signalling. Results TIGIT expression was elevated in patients with cervical cancer. High TIGIT expression in CD8+ T lymphocytes from patients with cervical cancer promotes the exhaustion of CD8+ T lymphocytes. In addition, CD155 is expressed at high levels in cervical cancer tissues and is negatively correlated with the level of infiltrating CD8+ T cells. We found that TIGIT, upon binding to CD155 and being phosphorylated, inhibited NF-κB and ERK activation by recruiting SHIP-1, resulting in the downregulation of cytokine production. Blocking TIGIT in activated CD8+ T cells attenuates the inhibitory effect of SHIP-1 on CD8+ T cells and enhances the activation of NF-κB and ERK. In vivo and in vitro experiments have proven that blocking TIGIT/CD155 restores the ability of CD8+ T cells to produce cytokines. Injecting the blocking antibody TIGIT in vivo inhibits tumour growth and enhances CD8+ T lymphocyte function. Treatment with a combination of TIGIT and PD-1 inhibitors further increases the efficacy of the TIGIT blocking antibody. Conclusions Our research shows that TIGIT/CD155 is a potential therapeutic target for cervical cancer.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer

et al. 2022

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“…These data led to a mathematical model that describes effects of valency and IgG subclass on in vivo function (135). The differential binding due to a change in the size of immune complex can potentially lead to substantial changes in cell signaling and recent technical advances provide a means to quantitate signaling with cell-based assays (136).…”

Section: How Multivalency Impacts Igg-fcγr Interactionsmentioning

confidence: 99%

Multiple Variables at the Leukocyte Cell Surface Impact Fc γ Receptor-Dependent Mechanisms

2019

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Fc γ receptors (FcγR) expressed on the surface of human leukocytes bind clusters of immunoglobulin G (IgG) to induce a variety of responses. Many therapeutic antibodies and vaccine-elicited antibodies prevent or treat infectious diseases, cancers and autoimmune disorders by binding FcγRs, thus there is a need to fully define the variables that impact antibody-induced mechanisms to properly evaluate candidate therapies and design new intervention strategies. A multitude of factors influence the IgG-FcγR interaction; one well-described factor is the differential affinity of the six distinct FcγRs for the four human IgG subclasses. However, there are several other recently described factors that may prove more relevant for disease treatment. This review covers recent reports of several aspects found at the leukocyte membrane or outside the cell that contribute to the cell-based response to antibody-coated targets. One major focus is recent reports covering post-translational modification of the FcγRs, including asparagine-linked glycosylation. This review also covers the organization of FcγRs at the cell surface, and properties of the immune complex. Recent technical advances provide high-resolution measurements of these often-overlooked variables in leukocyte function and immune system activation.

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“…Our methodology provides a comprehensive system, supporting the assessment of essentially all FcγRs, which presents an advantage over previously developed sIC detection and FcγR activation assays (Aoyama et al, 2019;Cheng et al, 2014;Hsieh et al, 2017;Stopforth et al, 2018;Szittner et al, 2016;Tada et al, 2014). In contrast to currently available commercial assays detecting sICs by C1q-CIC or C3d ELISA in the micromolar range, our assay measures overall sIC bioactivity in the nanomolar range and has a sole specificity for IgG sICs.…”

Section: Discussionmentioning

confidence: 99%

“…Therefore, an assay platform allowing for the systematic functional assessment of IC-mediated FcγR activation is strongly required. While a previously developed cell-based assay addresses sIC-mediated activation of the inhibitory FcγRIIB ( 36 ), a platform allowing for the comprehensive analysis of all FcγRs is missing.…”

Section: Introductionmentioning

confidence: 99%

Detection and functional resolution of soluble multimeric immune complexes by a comprehensive FcγR reporter cell panel

Chen

Maul-Pavicic

Holzer

et al. 2020

Preprint

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Fcγ-receptor (FcγR) activation by antibody derived soluble immune complexes (sICs) is a major contributor to inflammation in autoimmune diseases such as systemic lupus erythematosus (SLE). A robust and scalable test system allowing for the detection and quantification of sICs with regard to receptor activation is missing. We developed a comprehensive cell-based reporter system capable of measuring the sIC-mediated activation of individual human and mouse FcγRs. We show that compared to human FcγRs IIB and III, human FcγRs I and IIA lack sensitivity to sICs. Further, the assay proved to be sensitive to sIC size enabling us to demonstrate for the first time a complete translation of the Heidelberger-Kendall precipitation curve to FcγR responsiveness. The assay also proved useful to quantify sICs-mediated FcγR activation using sera from SLE patients and mouse models of lupus and arthritis. Thus, in clinical practice, it might be employed to measure FcγR activation as a biomarker for disease activity in immune-complex mediated disease.

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Detection of Experimental and Clinical Immune Complexes by Measuring SHIP-1 Recruitment to the Inhibitory FcγRIIB

Cited by 8 publications

References 57 publications

Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer

Blocking TIGIT/CD155 signalling reverses CD8+ T cell exhaustion and enhances the antitumor activity in cervical cancer

Multiple Variables at the Leukocyte Cell Surface Impact Fc γ Receptor-Dependent Mechanisms

Detection and functional resolution of soluble multimeric immune complexes by a comprehensive FcγR reporter cell panel

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