Selective Inhibition of T Cell Activation Via CD147 Through Novel Modulation of Lipid Rafts

Staffler, Günther; Szekeres, Andreas; Schütz, Gerhard J.; Säemann, Marcus D.; Prager, Elisabeth; Zeyda, Maximilian; Drbal, Karel; Zlabinger, Gerhard J.; Stulnig, Thomas M.; Stockinger, Hannes

doi:10.4049/jimmunol.171.4.1707

Cited by 52 publications

(70 citation statements)

References 55 publications

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“…Finally, exposure to minocycline or anti-EMMPRIN Abs reduced the surface levels of the T cell activation marker, CD25, as well as reduced levels of IFN-g and IL-10 from PBMCs (Fig. 4) (5). These similarities support the contention that minocycline may act, in part, through suppressing EMMPRIN-mediated pathways.…”

Section: Discussionsupporting

confidence: 67%

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Hahn

Kaushik

Mishra

et al. 2016

The Journal of Immunology

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Extracellular matrix metalloproteinase inducer (EMMPRIN, CD147) is a transmembrane glycoprotein that is upregulated on leukocytes in active lesions in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Administration of anti-EMMPRIN Abs reduces the severity of EAE. Minocycline is a tetracycline antibiotic with immune-modulatory properties that decreases the severity of EAE; it was recently found to attenuate the conversion from a first demyelinating event to clinically definite MS in a phase III trial. We investigated whether and how minocycline affects the expression of EMMPRIN on T cells in culture and in mice afflicted with EAE. EMMPRIN expression in cultures of mouse splenocytes or human PBMCs was elevated upon polyclonal T cell activation, and this was reduced by minocycline correspondent with decreased P-Akt levels. An established MS medication, IFN-β, also diminished EMMPRIN levels on human cells whereas this was not readily observed for fingolimod or monomethylfumarate. In EAE-afflicted mice, minocycline treatment significantly reduced EMMPRIN levels on splenic lymphocytes at the presymptomatic (day 7) phase, and prevented the development of disease. Day 7 spleen transcripts from minocycline-treated EAE mice had a significantly lower MMP-9/TIMP-1 ratio, and significantly lower MCT-1 and CD98 levels, factors associated with EMMPRIN function. Day 16 (peak clinical severity) CNS samples from EAE mice had prominent representation of inflammatory perivascular cuffs, inflammatory molecules and EMMPRIN, and these were abrogated by minocycline. Overall, minocycline attenuated the activation-induced elevation of EMMPRIN on T cells in culture and in EAE mice, correspondent with reduced immune function and EAE CNS pathology.

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Section: Discussionsupporting

confidence: 67%

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Hahn

Kaushik

Mishra

et al. 2016

The Journal of Immunology

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“…6A and 6B, CD147 silencing did not affect plasma membrane-expressed PMCA4 (SA pull-down). In addition to its shuttling function to the plasma membrane, we showed previously that CD147 influenced the lipid raft localization of CD48 and CD59 (14). However, density gradient centrifugation with CD147-silenced cells, stimulated or not with OKT3 plus Leu-28, showed that silencing of CD147 did not change the distribution of PMCA4 from the nonraft to the lipid raft compartment (Fig.…”

Section: Na(+)/k(+) Atpasementioning

confidence: 85%

“…Furthermore, CD147 was shown to influence T cell proliferation (10)(11)(12), thymocyte maturation (13), NFAT transcriptional activity, and IL-2 production (14,15). Recently, CD147 levels were described as a surrogate marker of activated regulatory T cells (16,17), and Abs specific to the extracellular domain of CD147 showed potent immunomodulatory capacities (11,18).…”

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confidence: 99%

Association of CD147 and Calcium Exporter PMCA4 Uncouples IL-2 Expression from Early TCR Signaling

Supper

Schiller

Paster

et al. 2016

The Journal of Immunology

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The Ig superfamily member CD147 is upregulated following T cell activation and was shown to serve as a negative regulator of T cell proliferation. Thus, Abs targeting CD147 are being tested as new treatment strategies for cancer and autoimmune diseases. How CD147 mediates immunosuppression and whether association with other coreceptor complexes is needed have remained unknown. In the current study, we show that silencing of CD147 in human T cells increases IL-2 production without affecting the TCR proximal signaling components. We mapped the immunosuppressive moieties of CD147 to its transmembrane domain and Ig-like domain II. Using affinity purification combined with mass spectrometry, we determined the domain specificity of CD147 interaction partners and identified the calcium exporter plasma membrane calcium ATPase isoform 4 (PMCA4) as the interaction partner of the immunosuppressive moieties of CD147. CD147 does not control the proper membrane localization of PMCA4, but PMCA4 is essential for the CD147-dependent inhibition of IL-2 expression via a calcium-independent mechanism. In summary, our data show that CD147 interacts via its immunomodulatory domains with PMCA4 to bypass TCR proximal signaling and inhibit IL-2 expression

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“…Recently, increased expression of CD147 was observed on CD3+ T cells from systemic lupus erythematosus patients compared to healthy donor T cells, likely indicating their increased activation (Pistol et al 2007). Engagement of CD147 with the MEM-M6/6 anti-CD147 monoclonal antibody was found to inhibit anti-CD3 induced T cell activation (Koch et al 1999), presumably by inhibiting the reorganization and clustering of GPI-anchored coreceptors within lipid rafts which in turn alters down-stream signaling events (Staffler et al 2003). For T cells, the level of CD147 expression also correlates with the state of differentiation, whereby immature thymocytes express higher CD147 levels than do mature resting T cells (Kirsch et al 1997).…”

Section: Role In Lymphocyte Migration and Activationmentioning

confidence: 99%

CD147 immunoglobulin superfamily receptor function and role in pathology

Iacono

Brown

Greene

et al. 2007

Experimental and Molecular Pathology

244

206

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The immunoglobulin superfamily member CD147 plays an important role in fetal, neuronal, lymphocyte and extracellular matrix development. Here we review the current understanding of CD147 expression and protein interactions with regard to CD147 function and its role in pathologic conditions including heart disease, Alzheimer's disease, stroke and cancer. A model linking hypoxic conditions found within the tumor microenvironment to up-regulation of CD147 expression and tumor progression is introduced.

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Selective Inhibition of T Cell Activation Via CD147 Through Novel Modulation of Lipid Rafts

Cited by 52 publications

References 55 publications

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Impact of Minocycline on Extracellular Matrix Metalloproteinase Inducer, a Factor Implicated in Multiple Sclerosis Immunopathogenesis

Association of CD147 and Calcium Exporter PMCA4 Uncouples IL-2 Expression from Early TCR Signaling

CD147 immunoglobulin superfamily receptor function and role in pathology

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