IkappaBzeta regulates T(H)17 development by cooperating with ROR nuclear receptors.
Interleukin (IL)-17-producing helper T (T(H)17) cells are a distinct T-cell subset characterized by its pathological role in autoimmune diseases. IL-6 and transforming growth factor-beta (TGF-beta) induce T(H)17 development, in which the orphan nuclear receptors, RORgammat and RORalpha, have an indispensable role. However, in the absence of IL-6 and TGF-beta, the ectopic expression of RORgammat or RORalpha leads to only a modest IL-17 production. Here we identify a nuclear IkappaB family member, IkappaBzeta (encoded by the Nfkbiz gene), as a transcription factor required for T(H)17 development in mice. The ectopic expression of IkappaBzeta in naive CD4(+) T cells together with RORgammat or RORalpha potently induces T(H)17 development, even in the absence of IL-6 and TGF-beta. Notably, Nfkbiz(-/-) mice have a defect in T(H)17 development and a resistance to experimental autoimmune encephalomyelitis (EAE). The T-cell-intrinsic function of IkappaBzeta was clearly demonstrated by the resistance to EAE of the Rag2(-/-) mice into which Nfkbiz(-/-) CD4(+) T cells were transferred. In cooperation with RORgammat and RORalpha, IkappaBzeta enhances Il17a expression by binding directly to the regulatory region of the Il17a gene. This study provides evidence for the transcriptional mechanisms underlying T(H)17 development and points to a molecular basis for a novel therapeutic strategy against autoimmune disease.
Okamoto
Kazuo
K
Department of Cell Signaling, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Japan.
Iwai
Yoshiko
Y
Oh-Hora
Masatsugu
M
Yamamoto
Masahiro
M
Morio
Tomohiro
T
Aoki
Kazuhiro
K
Ohya
Keiichi
K
Jetten
Anton M
AM
Akira
Shizuo
S
Muta
Tatsushi
T
Takayanagi
Hiroshi
H
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018920:Coculture Techniques; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism; D005786:Gene Expression Regulation; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000235:genetics / Q000378:metabolism*; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism*; D014158:Transcription, Genetic
D048868:Adaptor Proteins, Signal Transducing; D020381:Interleukin-17; D052002:NF-kappa B p50 Subunit; C485947:Nfkbiz protein, mouse; D009687:Nuclear Proteins; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3
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