Transcription Factor Early Growth Response 3 Is Associated with the TGF-β1 Expression and the Regulatory Activity of CD4-Positive T Cells In Vivo
Copyright policy )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.
- University of Tokyo Japan
- Showa General Hospital Japan
CD4-Positive T-Lymphocytes, Mice, Knockout, Mice, Inbred BALB C, Reverse Transcriptase Polymerase Chain Reaction, Enzyme-Linked Immunosorbent Assay, Cell Separation, Flow Cytometry, Real-Time Polymerase Chain Reaction, Mice, Inbred C57BL, Transforming Growth Factor beta1, Mice, Gene Expression Regulation, Animals, Humans, Early Growth Response Protein 3
CD4-Positive T-Lymphocytes, Mice, Knockout, Mice, Inbred BALB C, Reverse Transcriptase Polymerase Chain Reaction, Enzyme-Linked Immunosorbent Assay, Cell Separation, Flow Cytometry, Real-Time Polymerase Chain Reaction, Mice, Inbred C57BL, Transforming Growth Factor beta1, Mice, Gene Expression Regulation, Animals, Humans, Early Growth Response Protein 3
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