Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling
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
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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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 9

Moesin loss potentiates adoptive T cell therapy of melanoma.

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Moesin loss potentiates adoptive T cell therapy of melanoma. (A) Treatme...
(A) Treatment scheme for B6 mice injected s.c. with B16-F1 melanoma tumor cells (2.5 × 105) 7 days before lymphodepletion with 6 Gy total-body irradiation and adoptive cell transfer (ACT) of 2 × 106 Pmel-1 T cells (i.v.) at day 8. (B) Tumor growth kinetics in individual mice treated as indicated in A; WT, n = 6; Msn KO, n = 4. (C) Frequency of donor Pmel-1 CD8+ T cells in the blood of WT and Msn KO mice from B at 8 weeks. (D) Survival analysis of WT and Msn KO mice upon tumor injection and adoptive T cell transfer. (E) B6.Rag2–/– mice treated as in A and ACT (i.v.) on day 8 with 2 × 106 Pmel-1 T cells coinfused with CD4+CD25– T cells isolated from WT (CD45.1, black) or Msn KO (CD45.2, red) bone marrow chimeric mice. WT CD45.1 are from WT>WT bone marrow chimeric mice and CD45.2 are from Msn KO>WT chimeric mice reconstituted for 8 weeks. (F) Tumor growth kinetics in mice treated as indicated in E. (G and H) Tumor weight and percentage of tumor-infiltrating Pmel-1 CD8+ T cells at endpoint. (I and J) Endpoint analysis of the tumor-infiltrating lymphocytes (TILs) for FOXP3+ iTregs in the tumor (I) and expression of TβRII on CD4+ TILs (J). (K and L) The spleen of tumor-bearing mice analyzed for FOXP3+ iTregs (K) and TβRII expression on splenic CD4+ T cells (L). n = 5 per group. Data are reported as the mean ± SEM. *P < 0.05, **P = 0.01, ***P = 0.001 by Student’s t test (C and G–L), by Mann-Whitney test (B and F), or by log-rank test (D).