title: Transcription factor early growth response 3 is associated with the TGF-β1 expression and the regulatory activity of CD4-positive T cells in vivo.
abstract: TGF-β1 is an important anti-inflammatory cytokine, and several regulatory T cell (Treg) subsets including CD4(+)CD25(+)Foxp3(+) Tregs and Th3 cells have been reported to exert regulatory activity via the production of TGF-β1. However, it has not yet been elucidated which transcription factor is involved in TGF-β1 transcription. Early growth response 3 (Egr-3) is a zinc-finger transcription factor that creates and maintains T cell anergy. In this study, we found that Egr-3 induces the expression of TGF-β1 in both murine and human CD4(+) T cells. Egr-3 overexpression in murine CD4(+) T cells induced the production of TGF-β1 and enhanced the phosphorylation of STAT3, which is associated with TGF-β1 transcription. Moreover, Egr-3 conferred Ag-specific regulatory activity on murine CD4(+) T cells. In collagen-induced arthritis and delayed-type hypersensitivity model mice, Egr-3-transduced CD4(+) T cells exhibited significant regulatory activity in vivo. In particular, the suppression of delayed-type hypersensitivity depended on TGF-β1. In human tonsils, we found that CD4(+)CD25(-)CD45RO(-)lymphocyte activation gene 3 (LAG3)(-) T cells express membrane-bound TGF-β1 in an EGR3-dependent manner. Gene-expression analysis revealed that CD4(+)CD25(-)CD45RO(-)LAG3(-) T cells are quite different from conventional CD4(+)CD25(+)Foxp3(+) Tregs. Intriguingly, the CD4(+)CD25(-)CD45RO(-)LAG3(-) T cells suppressed graft-versus-host disease in immunodeficient mice transplanted with human PBMCs. Our results suggest that Egr-3 is a transcription factor associated with TGF-β1 expression and in vivo regulatory activity in both mice and humans.
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Shuji
authors.initials: S
authors.lastname: Sumitomo
authors.forename: Keishi
authors.initials: K
authors.lastname: Fujio
authors.forename: Tomohisa
authors.initials: T
authors.lastname: Okamura
authors.forename: Kaoru
authors.initials: K
authors.lastname: Morita
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Ishigaki
authors.forename: Keigo
authors.initials: K
authors.lastname: Suzukawa
authors.forename: Kaori
authors.initials: K
authors.lastname: Kanaya
authors.forename: Kenji
authors.initials: K
authors.lastname: Kondo
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Yamasoba
authors.forename: Asayo
authors.initials: A
authors.lastname: Furukawa
authors.forename: Noburou
authors.initials: N
authors.lastname: Kitahara
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Shoda
authors.forename: Mihoko
authors.initials: M
authors.lastname: Shibuya
authors.forename: Akiko
authors.initials: A
authors.lastname: Okamoto
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation; D051776:Early Growth Response Protein 3 / Q000276:immunology / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053773:Transforming Growth Factor beta1 / Q000096:biosynthesis* / Q000276:immunology
chemical_list: C079945:EGR3 protein, human; C497369:Egr3 protein, mouse; D053773:Transforming Growth Factor beta1; D051776:Early Growth Response Protein 3