Foxp3 inhibits RORgammat-mediated IL-17A mRNA transcription through direct interaction with RORgammat.
The cytokine, transforming growth factor-beta1 (TGF-beta1), converts naive T cells into regulatory T cells that prevent autoimmunity. However, in the presence of interleukin (IL)-6, TGF-beta1 has also been found to promote differentiation into IL-17-producing helper T (Th17) cells that are deeply involved in autoimmunity and inflammation. However, it has not been clarified how TGF-beta1 and IL-6 determine such a distinct fate. Here we found that a master regulator for Th17, retinoic acid-related orphan receptor gammat (RORgammat), was rapidly induced by TGF-beta1 regardless of the presence of IL-6. IL-6 reduced Foxp3 expression, and overexpression of Foxp3 in a T cell line resulted in a strong reduction of IL-17A expression. We have characterized the IL-17A promoter and found that RORgammat binding is sufficient for activation of the minimum promoter in the HEK 293T cells. RORgammat-mediated IL-17A promoter activation was suppressed by forced expression of Foxp3. Foxp3 directly interacted with RORgammat through exon 2 region of Foxp3. The exon 2 region and forkhead (FKH) domain of Foxp3 were necessary for the suppression of RORgammat-mediated IL-17A promoter activation. We propose that induction of Foxp3 is the mechanism for the suppression of Th17 and polarization into inducible Treg.
Ichiyama
Kenji
K
Division of Molecular and Cellular Immunology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan.
Yoshida
Hideyuki
H
Wakabayashi
Yu
Y
Chinen
Takatoshi
T
Saeki
Kazuko
K
Nakaya
Mako
M
Takaesu
Giichi
G
Hori
Shohei
S
Yoshimura
Akihiko
A
Kobayashi
Takashi
T
D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D006801:Humans; D020381:Interleukin-17 / Q000737:chemistry*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018168:Receptors, Retinoic Acid / Q000737:chemistry*; D011988:Receptors, Thyroid Hormone / Q000737:chemistry*; D012689:Sequence Homology, Nucleic Acid; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic
C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse