Intranuclear interactomic inhibition of FoxP3 suppresses functions of Treg cells

Jong Hyun Park; Ji Seung Ko; Yoonchul Shin; Jen Young Cho; Han Ah Oh; Alfred M. Bothwell; Sang Kyou Lee

doi:10.1016/j.bbrc.2014.06.141

Intranuclear interactomic inhibition of FoxP3 suppresses functions of Treg cells

Jong Hyun Park, Ji Seung Ko, Yoonchul Shin, Jen Young Cho, Han Ah Oh, Alfred M. Bothwell, Sang Kyou Lee

Department of Biotechnology

Research output: Contribution to journal › Article › peer-review

13 Citations (Scopus)

Abstract

Regulatory T cells (Treg cells) are crucial for the maintenance of immunological tolerance, and it has been reported that Treg cells are enriched within the tumor micro-environment for immune evasion due to their immunosuppressive functions. To inhibit Treg cells functions, FoxP3, a lineage-specific transcription factor responsible for the differentiation and functions of Treg cells, was functionally targeted by a nucleus-transducible (nt) form of various FoxP3 functional subdomains. These nt modified domains can be delivered into the nucleus effectively and work as interactomic inhibitors via disruption of the endogenous FoxP3-mediated transcription complex. Among these domains, nt-FoxP3-FKH (Forkhead DNA binding domain) is most effective at restoring NFAT activity suppressed by FoxP3, and inhibiting the binding of endogenous FKH-containing proteins to FKH DNA binding sequences without influencing the viability and activation of T cells. The suppressive functions of TGF-β-induced iTreg cells and thymus-derived tTreg cells were substantially blocked by nt-FoxP3-FKH, accompanied with down-regulation of CTLA-4 surface expression and IL-10 secretion of Treg cells. In addition, nt-FoxP3-FKH upregulated the expression of IL-2 and IFN-γ in Treg cells. Therefore, nt-FoxP3-FKH has the potential to be a novel therapeutic agent to modulate the immune-evasive tumor environment created by Treg cells without the need for genetic modifications.

Original language	English
Pages (from-to)	1-7
Number of pages	7
Journal	Biochemical and Biophysical Research Communications
Volume	451
Issue number	1
DOIs	https://doi.org/10.1016/j.bbrc.2014.06.141
Publication status	Published - 2014 Aug 15

Bibliographical note

Funding Information:
This work was supported in part by a grant from the Translational Research Center for Protein Function Control , NRF ( 2009-0083522 ), Republic of Korea, and the Brain Korea 21 (BK21) PLUS program, J.-H. Park is fellowship awardee by BK21 PLUS program, Republic of Korea.

All Science Journal Classification (ASJC) codes

Biophysics
Biochemistry
Molecular Biology
Cell Biology

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10.1016/j.bbrc.2014.06.141

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title = "Intranuclear interactomic inhibition of FoxP3 suppresses functions of Treg cells",

abstract = "Regulatory T cells (Treg cells) are crucial for the maintenance of immunological tolerance, and it has been reported that Treg cells are enriched within the tumor micro-environment for immune evasion due to their immunosuppressive functions. To inhibit Treg cells functions, FoxP3, a lineage-specific transcription factor responsible for the differentiation and functions of Treg cells, was functionally targeted by a nucleus-transducible (nt) form of various FoxP3 functional subdomains. These nt modified domains can be delivered into the nucleus effectively and work as interactomic inhibitors via disruption of the endogenous FoxP3-mediated transcription complex. Among these domains, nt-FoxP3-FKH (Forkhead DNA binding domain) is most effective at restoring NFAT activity suppressed by FoxP3, and inhibiting the binding of endogenous FKH-containing proteins to FKH DNA binding sequences without influencing the viability and activation of T cells. The suppressive functions of TGF-β-induced iTreg cells and thymus-derived tTreg cells were substantially blocked by nt-FoxP3-FKH, accompanied with down-regulation of CTLA-4 surface expression and IL-10 secretion of Treg cells. In addition, nt-FoxP3-FKH upregulated the expression of IL-2 and IFN-γ in Treg cells. Therefore, nt-FoxP3-FKH has the potential to be a novel therapeutic agent to modulate the immune-evasive tumor environment created by Treg cells without the need for genetic modifications.",

author = "Park, {Jong Hyun} and Ko, {Ji Seung} and Yoonchul Shin and Cho, {Jen Young} and Oh, {Han Ah} and Bothwell, {Alfred M.} and Lee, {Sang Kyou}",

note = "Funding Information: This work was supported in part by a grant from the Translational Research Center for Protein Function Control , NRF ( 2009-0083522 ), Republic of Korea, and the Brain Korea 21 (BK21) PLUS program, J.-H. Park is fellowship awardee by BK21 PLUS program, Republic of Korea.",

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AU - Oh, Han Ah

AU - Bothwell, Alfred M.

AU - Lee, Sang Kyou

N1 - Funding Information: This work was supported in part by a grant from the Translational Research Center for Protein Function Control , NRF ( 2009-0083522 ), Republic of Korea, and the Brain Korea 21 (BK21) PLUS program, J.-H. Park is fellowship awardee by BK21 PLUS program, Republic of Korea.

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Intranuclear interactomic inhibition of FoxP3 suppresses functions of Treg cells

Abstract

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