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 10

Schematic model on the roles of moesin in controlling optimal TGF-β signaling and promoting iTreg generation.

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Schematic model on the roles of moesin in controlling optimal TGF-β sign...
(i–iii) Under pathological conditions such as cancer, TGF-β production by tumor cells binds to cognate receptors on T cell surfaces and triggers signaling events that lead to FOXP3 expression and induced Treg development. (iv–vi) Signaling via the TGF-β noncanonical Akt/hnRNP E1 axis leads to post-transcriptional moesin expression. The TGF-β, Rho kinase, and/or phosphatidylinositol 4,5-bisphosphate[PtdIns(4,5)P2] signaling pathways lead to phosphorylation/activation of moesin and aid moesin binding to F-actin. (vii–ix) Moesin–F-actin binding may promote internalization of TGF-β receptors possibly via early endosomes, which feeds forward to promote optimal TGF-β signaling leading to efficient FOXP3 induction and iTreg differentiation. (x) Moesin may also promote efficient recycling of TGF-β receptors to maintain the abundance of TβRII on the cell surface. (xi and xii) Differentiated induced Tregs then suppress the proliferation of other immune cells such as cytotoxic T lymphocytes (CTLs) and effector T (Teff) cells to limit antitumor responses and promote tumor progression. PM, plasma membrane.