Cyclooxygenase Regulates Cell Surface Expression of CXCR3/1-Storing Granules in Human CD4+ T Cells

Gasser, Olivier; Schmid, Thomas; Zenhaeusern, Gabriela; Hess, Christoph

doi:10.4049/jimmunol.177.12.8806

Cited by 11 publications

(7 citation statements)

References 51 publications

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“…We subsequently turned our attention to the fate of CXCR3 following its internalization, using confocal microscopy to examine intracellular localisation of the receptor in permeablized T-lymphocytes. A predominantly granular intracellular staining pattern for CXCR3 was evident in untreated cells, (Figure 6A) identical to that previously described by Gasser and colleagues (44). Likewise, a similar pattern was seen for staining with the late endosome marker lamp-1 (Figure 6B) with little co-localisation of signals seen (Figure 6C).…”

Section: Resultssupporting

confidence: 86%

The Chemokine Receptor CXCR3 Is Degraded following Internalization and Is Replenished at the Cell Surface by De Novo Synthesis of Receptor

Meiser

Müeller

Wise

et al. 2008

The Journal of Immunology

115

114

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The chemokine receptor CXCR3 is expressed on the surface of both resting and activated T- lymphocytes. We describe here a study of the endocytosis of CXCR3 using T-lymphocytes and CXCR3 transfectants. Chemokine-induced CXCR3 downregulation occurred in a rapid, dose-dependent manner, with CXCL11 the most potent and efficacious ligand. Endocytosis was mediated in part by arrestins, but appeared to occur independently of clathrin and caveolae. In contrast to other chemokine receptors, which are largely recycled to the cell surface within an hour, cell surface replenishment of CXCR3 occurred over several hours and was dependent upon mRNA transcription, de novo protein synthesis and transport through the ER and Golgi. Confocal microscopy and Western blotting confirmed the fate of endocytosed CXCR3 to be degradation, mediated in part by lysosomes and proteosomes. Site-directed mutagenesis of the CXCR3 C-terminus revealed that internalization and degradation were independent of phophorylation, ubiquitination or a conserved LL motif. CXCR3 was found to be efficiently internalized in the absence of ligand, a process involving a YXXL motif at the extreme of the C-terminus. Although freshly isolated T-lymphocytes expressed moderate cell surface levels of CXCR3, they were only responsive to CXCL11 with CXCL9 and CXCL10 only having significant activity on activated T-lymphocytes. Thus, the activities of CXCR3 are tightly controlled following mRNA translation. Since CXCR3+ cells are themselves a source of IFN-γ, which potently induces the expression of CXCR3 ligands, such tight regulation of CXCR3 may serve as a control to avoid the unnecessary amplification of activated T-lymphocyte recruitment.

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Section: Resultssupporting

confidence: 86%

The Chemokine Receptor CXCR3 Is Degraded following Internalization and Is Replenished at the Cell Surface by De Novo Synthesis of Receptor

Meiser

Müeller

Wise

et al. 2008

The Journal of Immunology

115

114

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“…Known as a chemoattractant for neutrophils, CXCL8 can also recruit T cells, particularly activated or effector/memory T cell types 36 37 . The role of CXCL8 in the pathogenesis of OLP requires further study because there are conflicting reports regarding its expression in OLP tissues 21 38 .…”

Section: Discussionmentioning

confidence: 99%

The presence of bacteria within tissue provides insights into the pathogenesis of oral lichen planus

Choi

Kim

Yoon

et al. 2016

Sci Rep

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Oral lichen planus (OLP) is a chronic T cell-mediated mucocutaneous disease of unknown etiopathogenesis. Although various antigens have been considered, what actually triggers the inflammatory response of T cells is unknown. In the present study, we propose that intracellular bacteria present within tissues trigger T cell infiltration and provide target antigens. Sections of OLP (n = 36) and normal (n = 10) oral mucosal tissues were subjected to in situ hybridization using a universal probe targeting the bacterial 16S rRNA gene and immunohistochemistry with anti-CD3, anti-CD4, anti-CD8, and anti-macrophage-specific antibodies. Bacteria were abundant throughout the epithelium and the lamina propria of OLP tissues, which exhibited positive correlations with the levels of infiltrated CD3+, CD4+, and CD8+ cells. Furthermore, bacteria were detected within the infiltrated T cells. Pyrosequencing analysis of the mucosal microbiota from OLP patients (n = 13) and control subjects (n = 11) revealed a decrease in Streptococcus and increases in gingivitis/periodontitis-associated bacteria in OLP lesions. Using the selected bacterial species, we demonstrated that certain oral bacteria damage the epithelial physical barrier, are internalized into epithelial cells or T cells, and induce production of T cell chemokines CXCL10 and CCL5. Our findings provide insights into the pathogenesis of OLP.

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“…Initial studies demonstrated that resting human T cells expressed little CXCR3, but this receptor was expressed by the majority of T cells after mitogenic activation for 72 h by culturing with the immobilised CD3 antibody, OKT3. Indeed, previous studies have shown that CXCR3 is stored by resting T cells in cytoplasmic granules allowing release onto the cell-surface within minutes of activation (Gasser et al, 2006). This chemokine receptor was shown to function in transendothelial chemotaxis assays in which the ligand CXCL10 was added below the endothelial cell monolayer.…”

Section: Discussionmentioning

confidence: 99%

T cell extravasation: Demonstration of synergy between activation of CXCR3 and the T cell receptor

Newton

O'Boyle

Jenkins

et al. 2009

Molecular Immunology

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Endothelial cells present chemokines to T cells and can also stimulate the T cell antigen receptor by presentation of peptide–MHC antigen complexes. This study was designed to investigate the potential synergy between stimulation of the chemokine receptor CXCR3 and the human T cell receptor complex. Transendothelial T cell migration towards CXCL10 was modified by crosslinking CD3 immediately before addition to the endothelium. When resting endothelium was used, T cells which had been activated by crosslinking CD3 for only 1 min showed a significant reduction (p < 0.0001) in migration when compared with untreated T cells. By contrast, endothelial cells which had been activated by stimulation with interferon-γ and tumour necrosis factor-α supported a specific increase in the migration of activated T cells; this was most apparent after CD3 had been activated for 90 min (p < 0.0001). The molecular basis for synergy between CXCR3 and the T cell receptor complex was investigated by measurement of fluorescence resonance energy transfer. This showed that CXCL10 induced a close (<10 nm) spatial association between CXCR3 and the CD3ɛ subunit on the cell-surface. These data demonstrate that stimulation of both CXCR3 and the T cell receptor has the potential to enhance specifically both the proliferation and extravasation of specific T cells during episodes of local inflammation.

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Cyclooxygenase Regulates Cell Surface Expression of CXCR3/1-Storing Granules in Human CD4+ T Cells

Cited by 11 publications

References 51 publications

The Chemokine Receptor CXCR3 Is Degraded following Internalization and Is Replenished at the Cell Surface by De Novo Synthesis of Receptor

The Chemokine Receptor CXCR3 Is Degraded following Internalization and Is Replenished at the Cell Surface by De Novo Synthesis of Receptor

The presence of bacteria within tissue provides insights into the pathogenesis of oral lichen planus

T cell extravasation: Demonstration of synergy between activation of CXCR3 and the T cell receptor

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