Functional Expression of a Costimulatory B7.2 (CD86) Protein on Human Salivary Gland Epithelial Cells that Interacts with the CD28 Receptor, but Has Reduced Binding to CTLA4

Kapsogeorgou, Efstathia K.; Moutsopoulos, Haralampos Μ.; Manoussakis, Menelaos N.

doi:10.4049/jimmunol.166.5.3107

Cited by 85 publications

(90 citation statements)

References 49 publications

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“…20 Later studies from the same research group proved constitutive expression of B7.2 molecules is sufficient to provide costimulatory signals to anti-CD3-stimulated T cells, implying a critical role for epithelial cells in the regulation of local immune responses in the salivary glands. 21,22 Evidence of the involvement of B7-H4 in the pathogenesis of various autoimmune disorders has been reported. 15 In our previous study, we found B7-H4 was not expressed on lymphocytes but on SGECs and the expression in pSS patients was lower than that in nonpSS controls, 16 adding the defect of B7-H4 expression on SGECs to the infiltration of lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

B7‐H4 deficiency in salivary gland of patients with primary Sjögren's syndrome impairs the regulatory effect on T cells

Yu²,

et al. 2017

Int J of Rheum Dis

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Aim: Our previous study confirmed the defect of B7-H4 expression in peripheral blood and salivary glands of patients with primary Sj€ ogren's syndrome (pSS). The aim of this study was to analyze the effect of the deficit expression of B7-H4 on CD4 + T cells.Methods: CD4 + T cells were purified by magnetic-activated cell sorting MACS. The proliferation and cytokine production of CD4 + T cells co-cultured with purified salivary gland epithelial cells (SGECs) from pSS or non-SS sicca syndrome were detected.Results: By co-culturing the gland cells with CD4 + T cells, we found the proliferation of CD4 + T cells was significantly suppressed. The effect was weaker when SGECs from pSS patients were used compared to that from nonpSS sicca syndrome controls. Simultaneously, the productions of cytokines interleukin (IL)-5, IL-13, IL-17A, IL-6 in supernatant were reduced and also SGECs from pSS patients decreased them less than that from non-SS controls. Conclusions:The decrease of B7-H4 expression in salivary glands of SS patients contributes to the defect of negatively regulating the inflammation caused by CD4 + T cells, thereby providing new insights into the role of B7-H4 in the inflammatory process of salivary glands in SS.

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Section: Discussionmentioning

confidence: 99%

B7‐H4 deficiency in salivary gland of patients with primary Sjögren's syndrome impairs the regulatory effect on T cells

Yu²,

et al. 2017

Int J of Rheum Dis

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“…However, SGEC lines obtained from patients with Sjögren's syndrome have been shown to display a constitutively activated phenotype as suggested by the significantly increased spontaneous expression of several immunomodulatory molecules (including cytokines, chemokines, TLRs, and MHC, costimulatory, and adhesion molecules) compared with control SGEC lines from patients not found to have Sjögren's syndrome (17). Regarding B7-2 molecules, constitutive expression of the full-length B7-2 mRNA and protein is detectable in all SGEC lines (15). However, expression levels vary considerably among cell lines, ranging from low to high (albeit the latter are significantly lower compared with those of B cells, monocytes, and dendritic cells (DC)).…”

Section: Cell Linesmentioning

confidence: 99%

“…Previously, we have demonstrated that human non-neoplastic salivary gland epithelial cells (SGECs) 3 express functional fulllength and soluble protein forms of the B7-2 molecules (15). In this study, we describe the expression of a novel human B7-2 mRNA splicing variant by SGECs, as well as by peripheral blood monocytes.…”

mentioning

confidence: 96%

“…B cell purity was routinely Ͼ98%, as determined by flow cytometric analysis using FITC-labeled anti-CD20 mAb. CD4 ϩ T cells were purified from T cell-enriched PBMC by immunomagnetic positive selection using Dynabeads M450-coated with anti-CD4 (Dynal Biotech), as previously described (15). By flow cytometry, the purity of CD4 ϩ T cell population yields was routinely Ͼ99.3%, and the isolated CD4 ϩ T cells showed minimal expression of CD25 (IL-2R␣, Ͻ5% positive), whereas they were unresponsive to stimulation by anti-CD3 mAb only.…”

Section: Isolation Of Peripheral Blood Subpopulationsmentioning

confidence: 99%

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A Novel B7-2 (CD86) Splice Variant with a Putative Negative Regulatory Role

Kapsogeorgou

Moutsopoulos

Manoussakis

2008

The Journal of Immunology

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B7-2 (CD86) costimulatory molecules are pivotal for the regulation of T cell responses. In this study, a novel human B7-2 alternate transcript (termed B7-2C) is described. This transcript is characterized by the deletion of exon 4 that encodes the IgV-like counter-receptor binding domain of the B7-2 protein (full-length; B7-2A). B7-2C was detected as mRNA and cell surface protein in human non-neoplastic salivary gland epithelial cells and monocytes, but not in fibroblasts, T cells, B cells, dendritic cells, and several epithelial tumor cell lines. In monocytes, B7-2C protein expression was found to be significantly down-regulated following activation. The analysis of Chinese hamster ovary (CHO) single-transfected (CHO-B7-2C) and double-transfected (CHO-B7-2A/B7-2C) cell lines had indicated that cell surface B7-2C expression is by itself unable to provide T cell costimulation, but inhibits the transmission of costimulatory signals via B7-2A (by 23–69%). Such inhibition was found to depend on the relative cell surface expression of B7-2A and B7-2C proteins, as it occurred in CHO-B7-2A/B7-2C transfectants with significantly lower B7-2A to B7-2C ratios (1.0–3.5), compared with those with unaffected B7-2A-mediated costimulatory function (10.0–19.5). Our findings suggest that B7-2C is expressed by monocytes, as well as by nonimmune cells with potential Ag-presenting capacity (such as salivary gland epithelial cells). The expression of B7-2C on certain B7-2A-expressing cells appears to represent a mechanism for the fine tuning of B7-2A-mediated costimulatory signals, possibly through the interruption of B7-2A clustering required for the productive interaction between B7-2A and cognate receptors.

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“…The epithelial origin of cultured cells was routinely confirmed by staining with mAbs against epithelialspecific markers, including the various cytokeratins and epithelial membrane antigens and the absence of myoepithelial, fibroblastoid and lymphoid markers, using immunocytochemistry as previously described. 36,37 Evaluation of Furin, TACE and AREG Expression Cell Treatment SGEC were collected from culture media by centrifugation at 250 Â g and resuspended at 1 Â 10 6 cells/ml in McCoy's 5a modified medium. Cell suspensions (10 5 cells/well) were added to each well of a six-well plate (Thomas Scientific, Swedesboro, NJ, USA) and allowed to incubate for 24 h at 371C under 5% CO 2 .…”

Section: Microdissection and Primary Explant Culturementioning

confidence: 99%

Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies

et al. 2010

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The aim of this study was to analyze the Furin-TNF-a-converting enzyme (TACE)-amphiregulin (AREG)-IL-6/IL-8 secretion pathway in non-neoplastic human salivary gland epithelial cells (SGECs) stimulated with anti-Ro/SSA autoantibodies (Abs). We examined whether anti-Ro/SSA Abs-mediated TACE activation is responsible for AREG activation. As recent studies have demonstrated that AREG could induce proinflammatory cytokines secretion in epithelial cells, we discuss how TACE-mediated AREG shedding, caused by anti-Ro/SSA Abs treatment, could have a critical role in TNF-a-induced IL-6 and IL-8 secretion by SGEC. Furthermore, the effects of TNF-a blockade on AREG expression and TNF-a-AREGmediated IL-6 and IL-8 secretion were evaluated. We have discovered that the upregulation of AREG occurs through TNF-a produced after anti-Ro/SSA Abs uptake via Fcg receptors. Biological drug adalimumab and the gene silencing technique were used to study the AREG-IL-6/IL-8 secretion pathway, demonstrating that (i) adalimumab-mediated TNF-a blocking and TNF-a gene silencing provoke a significant decrease of proinflammatory cytokines production and AREG expression in anti-Ro/SSA Abs-treated SGEC; (ii) AREG gene silencing has a potent inhibitory effect on TNF-a-induced IL-6 and IL-8 secretion in SGEC treated with anti-Ro/SSA Abs; (iii) an inspection of the kinetics of cytokine production after exogeni TNF-a and AREG addition, and the use of cycloheximide in the presence of exogenous TNF-a as stimulant, clarified that TNF-a induces IL-6 and IL-8 secretion through AREG.

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Functional Expression of a Costimulatory B7.2 (CD86) Protein on Human Salivary Gland Epithelial Cells that Interacts with the CD28 Receptor, but Has Reduced Binding to CTLA4

Cited by 85 publications

References 49 publications

B7‐H4 deficiency in salivary gland of patients with primary Sjögren's syndrome impairs the regulatory effect on T cells

B7‐H4 deficiency in salivary gland of patients with primary Sjögren's syndrome impairs the regulatory effect on T cells

A Novel B7-2 (CD86) Splice Variant with a Putative Negative Regulatory Role

Blockade of TNF-α signaling suppresses the AREG-mediated IL-6 and IL-8 cytokines secretion induced by anti-Ro/SSA autoantibodies

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