CD147 in regulatory T cells

Landskron, Johannes; Taskén, Kjetil

doi:10.1016/j.cellimm.2013.04.008

Cited by 31 publications

(23 citation statements)

References 36 publications

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“…Both MM and MDS are malignancies of the bone marrow, which is characterized by a hypoxic microenvironment and the need for anaerobic glycolysis for energy production, making lactate export essential 40 . Moreover, because recent evidence suggests a negative regulatory role of CD147 in T cell-mediated immune responses [41][42][43] , it is tempting to speculate that IMiD-induced CD147 destabilization and subsequent inhibition of negative T cell regulation may contribute to IMiD-induced immune cell activation.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity

Eichner

Heider

Fernández‐Sáiz

et al. 2016

Nat Med

159

158

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Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity

Eichner

Heider

Fernández‐Sáiz

et al. 2016

Nat Med

159

158

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Section: Clinical Applications Of Cd147mentioning

confidence: 99%

“…The potential application of CD147 is not only as a marker of activated regulatory T cells [175] but also as a potential diagnostic marker of early stage diseases. The pivotal role of CD147, which reaches beyond that of a mere marker of inflammation, is demonstrated in the complex processes of atherogenesis, atheroprogression and acute atherosclerothrombosis [175]. The extra-endothelial expression of CD147 is a marker of the activity of lesions in multiple sclerosis, as this expression is present in leukocyte-containing perivascular cuffs but not in inactive lesions [122].…”

Section: Clinical Applications Of Cd147mentioning

confidence: 99%

The Biological Function and Clinical Utilization of CD147 in Human Diseases: A Review of the Current Scientific Literature

Xiong

Edwards

Zhou

2014

IJMS

187

194

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CD147 or EMMPRIN is a member of the immunoglobulin superfamily in humans. It is widely expressed in human tumors and plays a central role in the progression of many cancers by stimulating the secretion of matrix metalloproteinases (MMPs) and cytokines. CD147 regulates cell proliferation, apoptosis, and tumor cell migration, metastasis and differentiation, especially under hypoxic conditions. CD147 is also important to many organ systems. This review will provide a detailed overview of the discovery, characterization, molecular structure, diverse biological functions and regulatory mechanisms of CD147 in human physiological and pathological processes. In particular, recent studies have demonstrated the potential application of CD147 not only as a phenotypic marker of activated regulatory T cells but also as a potential diagnostic marker for early-stage disease. Moreover, CD147 is recognized as an effective therapeutic target for hepatocellular carcinoma (HCC) and other cancers, and exciting clinical progress has been made in HCC treatment using CD147-directed monoclonal antibodies.

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“…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).…”

mentioning

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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CD147 in regulatory T cells

Cited by 31 publications

References 36 publications

Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity

Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity

The Biological Function and Clinical Utilization of CD147 in Human Diseases: A Review of the Current Scientific Literature

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

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