Foxo1 and Foxp1 Play Opposing Roles in Regulating the Differentiation and Antitumor Activity of T9 Cells Programmed by IL-7

Overview

Journal Sci Signal

Specialties Cell Biology
Physiology
Science

Date 2017 Oct 12

PMID 29018172

Citations 33

Authors

Enguang Bi

Xingzhe Ma

Yong Lu

Maojie Yang

Qiang Wang

Gang Xue

Jianfei Qian

Siqing Wang

Qing Yi

Affiliations

Soon will be listed here.

Abstract

Tumor-specific CD4 T helper 9 (T9) cells, so-called because of their production of the cytokine interleukin-9 (IL-9), are a powerful effector T cell subset for cancer immunotherapy. We found that pretreatment of naïve CD4 T cells with IL-7 further enhanced their differentiation into T9 cells and augmented their antitumor activity. IL-7 markedly increased the abundance of the histone acetyltransferase p300 by activating the STAT5 and PI3K-AKT-mTOR signaling pathways and promoting the acetylation of histones at the promoter. As a result, the transcriptional regulator Foxo1 was dephosphorylated and translocated to the nucleus, bound to the promoter, and induced the production of IL-9 protein. In contrast, Foxp1, which bound to the promoter in naïve CD4 T cells and inhibited expression, was outcompeted for binding to the promoter by Foxo1 and translocated to the cytoplasm. Furthermore, forced expression of Foxo1 or a deficiency in in CD4 T cells markedly increased the production of IL-9, whereas a deficiency in inhibited the ability of IL-7 to enhance the differentiation and antitumor activity of T9 cells. Thus, we identified the roles of Foxo1 as a positive regulator and Foxp1 as a negative regulator of T9 cell differentiation and antitumor activity, which may provide potential targets for cancer immunotherapy.

Citing Articles

Group 2 innate lymphoid cells derived IL-9 reduces macrophage apoptosis and attenuates acute lung injury in sepsis.

Zhong X, Jin J, Zhang H, Liu Z, Ren Y, Xiao Y Inflamm Res. 2025; 74(1):38.

PMID: 39945866 DOI: 10.1007/s00011-024-01978-2.

Targeting the osteoclastogenic cytokine IL-9 as a novel immunotherapeutic strategy in mitigating inflammatory bone loss in post-menopausal osteoporosis.

Sapra L, Saini C, Sharma S, Nanda D, Nilakhe A, Chattopadhyay N JBMR Plus. 2024; 8(11):ziae120.

PMID: 39399159 PMC: 11470976. DOI: 10.1093/jbmrpl/ziae120.

Locus of (IL-9) control: IL9 epigenetic regulation in cellular function and human disease.

Son A, Baral I, Falduto G, Schwartz D Exp Mol Med. 2024; 56(6):1331-1339.

PMID: 38825637 PMC: 11263352. DOI: 10.1038/s12276-024-01241-y.

Regulatory role of T helper 9/interleukin-9: Transplantation view.

Roostaee A, Yaghobi R, Afshari A, Jafarinia M Heliyon. 2024; 10(4):e26359.

PMID: 38420400 PMC: 10900956. DOI: 10.1016/j.heliyon.2024.e26359.

Identification of FOXP1 as a favorable prognostic biomarker and tumor suppressor in intrahepatic cholangiocarcinoma.

Tang C, Zhuang H, Tong H, Yu X, Chen J, Wang Q BMC Cancer. 2024; 24(1):137.

PMID: 38279090 PMC: 10811915. DOI: 10.1186/s12885-024-11882-x.

References

Rathmell J, Farkash E, Gao W, Thompson C . IL-7 enhances the survival and maintains the size of naive T cells. J Immunol. 2001; 167(12):6869-76. DOI: 10.4049/jimmunol.167.12.6869. View

Chang H, Sehra S, Goswami R, Yao W, Yu Q, Stritesky G . The transcription factor PU.1 is required for the development of IL-9-producing T cells and allergic inflammation. Nat Immunol. 2010; 11(6):527-34. PMC: 3136246. DOI: 10.1038/ni.1867. View

Tang J, Shen G, Wang S, Wan Y, Wei Y . IL-7 inhibits tumor growth by promoting T cell-mediated antitumor immunity in Meth A model. Immunol Lett. 2014; 158(1-2):159-66. DOI: 10.1016/j.imlet.2013.12.019. View

Morrissey P, Conlon P, Braddy S, Williams D, Namen A, Mochizuki D . Administration of IL-7 to mice with cyclophosphamide-induced lymphopenia accelerates lymphocyte repopulation. J Immunol. 1991; 146(5):1547-52. View

Goswami R, Kaplan M . Gcn5 is required for PU.1-dependent IL-9 induction in Th9 cells. J Immunol. 2012; 189(6):3026-33. PMC: 3436945. DOI: 10.4049/jimmunol.1201496. View

Ouyang W, Liao W, Luo C, Yin N, Huse M, Kim M . Novel Foxo1-dependent transcriptional programs control T(reg) cell function. Nature. 2012; 491(7425):554-9. PMC: 3771531. DOI: 10.1038/nature11581. View

Dardalhon V, Awasthi A, Kwon H, Galileos G, Gao W, Sobel R . IL-4 inhibits TGF-beta-induced Foxp3+ T cells and, together with TGF-beta, generates IL-9+ IL-10+ Foxp3(-) effector T cells. Nat Immunol. 2008; 9(12):1347-55. PMC: 2999006. DOI: 10.1038/ni.1677. View

McDonald P, Read K, Baker C, Anderson A, Powell M, Ballesteros-Tato A . IL-7 signalling represses Bcl-6 and the TFH gene program. Nat Commun. 2016; 7:10285. PMC: 4729877. DOI: 10.1038/ncomms10285. View

Huang J, Durum S, Muegge K . Cutting edge: histone acetylation and recombination at the TCR gamma locus follows IL-7 induction. J Immunol. 2001; 167(11):6073-7. DOI: 10.4049/jimmunol.167.11.6073. View

10.

Ochiai K, Maienschein-Cline M, Mandal M, Triggs J, Bertolino E, Sciammas R . A self-reinforcing regulatory network triggered by limiting IL-7 activates pre-BCR signaling and differentiation. Nat Immunol. 2012; 13(3):300-7. PMC: 4028049. DOI: 10.1038/ni.2210. View

11.

Purwar R, Schlapbach C, Xiao S, Kang H, Elyaman W, Jiang X . Robust tumor immunity to melanoma mediated by interleukin-9-producing T cells. Nat Med. 2012; 18(8):1248-53. PMC: 3518666. DOI: 10.1038/nm.2856. View

12.

van der Heide L, Smidt M . Regulation of FoxO activity by CBP/p300-mediated acetylation. Trends Biochem Sci. 2005; 30(2):81-6. DOI: 10.1016/j.tibs.2004.12.002. View

13.

Colombetti S, Levy F, Chapatte L . IL-7 adjuvant treatment enhances long-term tumor-antigen-specific CD8+ T-cell responses after immunization with recombinant lentivector. Blood. 2009; 113(26):6629-37. DOI: 10.1182/blood-2008-05-155309. View

14.

Barata J, Silva A, Brandao J, Nadler L, Cardoso A, Boussiotis V . Activation of PI3K is indispensable for interleukin 7-mediated viability, proliferation, glucose use, and growth of T cell acute lymphoblastic leukemia cells. J Exp Med. 2004; 200(5):659-69. PMC: 2212738. DOI: 10.1084/jem.20040789. View

15.

Stone E, Pepper M, Katayama C, Kerdiles Y, Lai C, Emslie E . ICOS coreceptor signaling inactivates the transcription factor FOXO1 to promote Tfh cell differentiation. Immunity. 2015; 42(2):239-251. PMC: 4334393. DOI: 10.1016/j.immuni.2015.01.017. View

16.

Takada K, Jameson S . Naive T cell homeostasis: from awareness of space to a sense of place. Nat Rev Immunol. 2009; 9(12):823-32. DOI: 10.1038/nri2657. View

17.

Vegran F, Berger H, Boidot R, Mignot G, Bruchard M, Dosset M . The transcription factor IRF1 dictates the IL-21-dependent anticancer functions of TH9 cells. Nat Immunol. 2014; 15(8):758-66. DOI: 10.1038/ni.2925. View

18.

Veldhoen M, Uyttenhove C, Van Snick J, Helmby H, Westendorf A, Buer J . Transforming growth factor-beta 'reprograms' the differentiation of T helper 2 cells and promotes an interleukin 9-producing subset. Nat Immunol. 2008; 9(12):1341-6. DOI: 10.1038/ni.1659. View

19.

Chung B, Dudl E, Toyama A, Barsky L, Weinberg K . Importance of interleukin-7 in the development of experimental graft-versus-host disease. Biol Blood Marrow Transplant. 2007; 14(1):16-27. DOI: 10.1016/j.bbmt.2007.07.015. View

20.

Pellegrini M, Mak T . Tumor immune therapy: lessons from infection and implications for cancer - can IL-7 help overcome immune inhibitory networks?. Eur J Immunol. 2010; 40(7):1852-61. DOI: 10.1002/eji.201040603. View