TY - JOUR
T1 - Transcription factor early growth response 3 is associated with the TGF-β1 expression and the regulatory activity of CD4-positive T cells in vivo
AU - Sumitomo, Shuji
AU - Fujio, Keishi
AU - Okamura, Tomohisa
AU - Morita, Kaoru
AU - Ishigaki, Kazuyoshi
AU - Suzukawa, Keigo
AU - Kanaya, Kaori
AU - Kondo, Kenji
AU - Yamasoba, Tatsuya
AU - Furukawa, Asayo
AU - Kitahara, Noburou
AU - Shoda, Hirofumi
AU - Shibuya, Mihoko
AU - Okamoto, Akiko
AU - Yamamoto, Kazuhiko
PY - 2013/9/1
Y1 - 2013/9/1
N2 - 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 delayedtype 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.
AB - 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 delayedtype 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.
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U2 - 10.4049/jimmunol.1202106
DO - 10.4049/jimmunol.1202106
M3 - Article
C2 - 23904169
AN - SCOPUS:84883397137
SN - 0022-1767
VL - 191
SP - 2351
EP - 2359
JO - Journal of Immunology
JF - Journal of Immunology
IS - 5
ER -