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.
authors.affiliation: Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Jong-Hyun
authors.initials: JH
authors.lastname: Park
authors.affiliation: Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Ji Seung
authors.initials: JS
authors.lastname: Ko
authors.affiliation: Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Yoonchul
authors.initials: Y
authors.lastname: Shin
authors.affiliation: Department of Immunobiology, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, CT 06519, USA; Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jen Young
authors.initials: JY
authors.lastname: Cho
authors.affiliation: Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea.
authors.forename: Han-ah
authors.initials: HA
authors.lastname: Oh
authors.forename: Alfred L M
authors.initials: AL
authors.lastname: Bothwell
authors.affiliation: Department of Immunobiology, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Alfred M
authors.initials: AM
authors.lastname: Bothwell
authors.affiliation: Translational Research Center for Protein Function Control, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea; Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 120-749, Republic of Korea. Electronic address: sjrlee@yonsei.ac.kr.
authors.forename: Sang-Kyou
authors.initials: SK
authors.lastname: Lee
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes; D060908:CTLA-4 Antigen; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors / Q000378:metabolism; D017434:Protein Structure, Tertiary; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000502:physiology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
chemical_list: D060908:CTLA-4 Antigen; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D007376:Interleukin-2; D050778:NFATC Transcription Factors; D016212:Transforming Growth Factor beta; D016753:Interleukin-10
keywords: Cancer immunotherapy; FoxP3; Intranuclear interactomic inhibitor of transcription factor; Protein transduction domain; Regulatory T cells