Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling
Ephraim A. Ansa-Addo, … , Bei Liu, Zihai Li
Ephraim A. Ansa-Addo, … , Bei Liu, Zihai Li
Published March 13, 2017
Citation Information: J Clin Invest. 2017;127(4):1321-1337. https://doi.org/10.1172/JCI89281.
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Research Article Immunology

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

Abstract

Moesin is a member of the ezrin-radixin-moesin (ERM) family of proteins that are important for organizing membrane domains and receptor signaling and regulating the migration of effector T cells. Whether moesin plays any role during the generation of TGF-β–induced Tregs (iTregs) is unknown. Here, we have discovered that moesin is translationally regulated by TGF-β and is also required for optimal TGF-β signaling that promotes efficient development of iTregs. Loss of moesin impaired the development and function of both peripherally derived iTregs and in vitro–induced Tregs. Mechanistically, we identified an interaction between moesin and TGF-β receptor II (TβRII) that allows moesin to control the surface abundance and stability of TβRI and TβRII. We also found that moesin is required for iTreg conversion in the tumor microenvironment, and the deletion of moesin from recipient mice supported the rapid expansion of adoptively transferred CD8+ T cells against melanoma. Our study establishes moesin as an important regulator of the surface abundance and stability of TβRII and identifies moesin’s role in facilitating the efficient generation of iTregs. It also provides an advancement to our understanding about the role of the ERM proteins in regulating signal transduction pathways and suggests that modulation of moesin is a potential therapeutic target for Treg-related immune disorders.

Authors

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

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Figure 8

Moesin stabilizes surface abundance of TβRII.

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Moesin stabilizes surface abundance of TβRII. (A and B) Primary CD4+ T c...
(A and B) Primary CD4+ T cells (A) and B220+ B cells (B) from the spleen of WT and Msn KO mice were treated with cyclohexamide at the indicated times and surface TβRII analyzed by flow cytometry. (C) Flow cytometry analysis of primary CD4+ T cells isolated from the spleen of WT and Msn KO mice, and treated with brefeldin A (BFA), 20 μg/ml, for up to 5 hours and then washed. Cell surface TβRII was left to recover for up to 12 hours prior to analysis. (D) Reconstituted 1:1 mix of WT (CD45.1, black) and Msn KO (CD45.2, red) bone marrow chimeric mice treated as in C. Data represent the mean ± SD of 3 independent experiments in triplicate. *P < 0.05, ***P < 0.001 by 2-way ANOVA.