Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling

Ansa-Addo, Ephraim; Zhang, Yongliang; Yang, Yi; Hussey, George S.; Howley, Breege V.; Salem, Mohammad; Riesenberg, Brian; Sun, Shaoli; Rockey, Don C.; Karvar, Serhan; Howe, Philip H.; Liu, Bei; Li, Zihai

doi:10.1172/jci89281

Cited by 54 publications

(55 citation statements)

References 49 publications

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“…A recent study showed that moesin is associated with early endosomes, which are located close to the membrane, and controls early-to-late endosome transport (53). Although the detailed mechanism by which moesin regulates IL-15-dependent pathways remains unknown, the decreased internalization of IL-15Ra observed in the absence of moesin may explain, in part, the attenuated IL-15-mediated signaling and is consistent with studies describing a role for moesin in cell surface receptor trafficking (26,54,55).…”

Section: Discussionsupporting

confidence: 80%

The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance

Satooka

Nagakubo

Satō

et al. 2017

The Journal of Immunology

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The ezrin-radixin-moesin (ERM) proteins are a family of membrane-associated proteins that link membrane proteins with actin filaments in the cell cortex and regulate many cellular processes, including cell shape determination, membrane transport, and signal transduction. Lymphocytes predominantly express two ERM members, ezrin and moesin. Mutations in the moesin gene in humans are associated with primary immunodeficiency with profound lymphopenia, and moesin-deficient mice exhibit a similar lymphopenia phenotype. In this study, we show that aging moesin-deficient mice develop a systemic lupus erythematosus-like autoimmune phenotype, which is characterized by elevated serum autoantibody levels and glomerulonephritis. Younger moesin-deficient mice exhibited elevated basal levels of several Ig isotypes and enhanced Ab affinity maturation upon immunization. Germinal center B cells and follicular helper T cells spontaneously accumulated in unimmunized mice, and CD8CD44CD122Ly49 regulatory T (CD8 Tregs) cells, which inhibit the expansion of follicular helper T cells, were severely reduced in these mice. Isolated CD8 Treg cells from moesin-deficient mice showed impaired proliferation in response to IL-15, which was accompanied by defects in STAT5 activation and IL-15Rα internalization, suggesting that moesin plays a key role in IL-15-mediated signaling. These findings underscore the importance of moesin in IL-15-dependent CD8 Treg cell homeostasis and, thus, the control of self-tolerance.

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Section: Discussionsupporting

confidence: 80%

The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance

Satooka

Nagakubo

Satō

et al. 2017

The Journal of Immunology

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“…Moreover, Th17 cell polarization was also inhibited responded to NCTD by impairing IL-6-stimualted STAT3 activation rather than TGF-β1-dependent Smad2/3 pathway. These results were consistent with the conclusion that NCTD has no influence on Treg cell differentiation because TGF-β1-Smad2/3 signaling is also responsible for Treg cell generation [49].…”

Section: Discussionsupporting

confidence: 91%

Norcantharin ameliorates the development of murine lupus via limiting STAT3-mediated IL-17-producing cell accumulation

Du¹,

Feng²,

He³

et al. 2020

Preprint

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Background: Systemic lupus erythematosus (SLE), a devastating autoimmune disorder, results from the aberrant T cell and B cell activation. Norcantharin(NCTD), a derivative of Cantharidin, is an efficacious anti-cancer drug, whereas the role of NCTD in SLE remains unknown. As a result, we aimed to investigate the therapeutic effect of NCTD on the development of murine lupus.Methods: MRL/MpJ and MRL/ lpr female mice were randomly divided into three groups and administered with vehicle control or NCTD at 1 mg/kg or 2 mg/kg. The mortality rate, auto-antibodies, kidney damage, immune complex deposition and lupus-related inflammation level were tested. Furthermore, the proportion of T/B cells or T cell subsets in splenocytes from each group was monitored using flow cytometry. Finally, double-negative (CD3+CD4-CD8-, DN) T cell proliferation and T helper 17 (Th17) cell differentiation in vitro as well as regulatory pathways were analyzed for NCTD treatment.Results: NCTD decreased mortality, the accumulation of anti-dsDNA, splenomegaly and inflammation level of lupus mice. In addition, NCTD-treated MRL/ lpr mice showed notably ameliorated renal involvement. Moreover, we found that NCTD reduced DN T cell proliferation and Th17 differentiation via mediating the activation of signal transducer and activator of transcription 3 (STAT3). Conclusions: NCTD effectively suppressed DN T cell proliferation and Th17 cell polarization, thus ultimately contributing to the attenuated the SLE development. Our results revealed that NCTD may be a promising therapeutic agent for SLE.

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“…TGF‐β superfamily has crucial roles in tissue development and differentiation, and modulates proliferation and differentiation of MSCs, acting as autocrine signals to sustain MSC function . TGF‐β signaling also induces regulatory T‐cells and suppresses inflammation . Collectively, these observations suggest that EVs produced by Lean‐MSCs might mitigate cellular injury by modulating multiple reparative pathways.…”

Section: Discussionmentioning

confidence: 96%

Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles

Eirin

Zhu

Woollard

et al. 2019

Stem Cells Translational Medicine

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Mesenchymal stem/stromal cells (MSCs) release extracellular vesicles (EVs), which shuttle proteins to recipient cells, promoting cellular repair. We hypothesized that cardiovascular risk factors may alter the pattern of proteins packed within MSC‐derived EVs. To test this, we compared the protein cargo of EVs to their parent MSCs in pigs with metabolic syndrome (MetS) and Lean controls. Porcine MSCs were harvested from abdominal fat after 16 weeks of Lean‐ or MetS‐diet ( n = 5 each), and their EVs isolated. Following liquid chromatography mass spectrometry proteomic analysis, proteins were classified based on cellular component, molecular function, and protein class. Five candidate proteins were validated by Western blot. Clustering analysis was performed to identify primary functional categories of proteins enriched in or excluded from EVs. Proteomics analysis identified 6,690 and 6,790 distinct proteins in Lean‐ and MetS‐EVs, respectively. Differential expression analysis revealed that 146 proteins were upregulated and 273 downregulated in Lean‐EVs versus Lean‐MSCs, whereas 787 proteins were upregulated and 185 downregulated in MetS‐EVs versus MetS‐MSCs. Proteins enriched in both Lean‐ and MetS‐EVs participate in vesicle‐mediated transport and cell‐to‐cell communication. Proteins enriched exclusively in Lean‐EVs modulate pathways related to the MSC reparative capacity, including cell proliferation, differentiation, and activation, as well as transforming growth factor‐β signaling. Contrarily, proteins enriched only in MetS‐EVs are linked to proinflammatory pathways, including acute inflammatory response, leukocyte transendothelial migration, and cytokine production. Coculture with MetS‐EVs increased renal tubular cell inflammation. MetS alters the protein cargo of porcine MSC‐derived EVs, selectively packaging specific proinflammatory signatures that may impair their ability to repair damaged tissues. stem cells translational medicine 2019;8:430–440

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Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling

Cited by 54 publications

References 49 publications

The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance

The ERM Protein Moesin Regulates CD8+ Regulatory T Cell Homeostasis and Self-Tolerance

Norcantharin ameliorates the development of murine lupus via limiting STAT3-mediated IL-17-producing cell accumulation

Metabolic Syndrome Interferes with Packaging of Proteins within Porcine Mesenchymal Stem Cell-Derived Extracellular Vesicles

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