The AP-1 transcription factor Batf controls T(H)17 differentiation.
Activator protein 1 (AP-1, also known as JUN) transcription factors are dimers of JUN, FOS, MAF and activating transcription factor (ATF) family proteins characterized by basic region and leucine zipper domains. Many AP-1 proteins contain defined transcriptional activation domains, but BATF and the closely related BATF3 (refs 2, 3) contain only a basic region and leucine zipper, and are considered to be inhibitors of AP-1 activity. Here we show that Batf is required for the differentiation of IL17-producing T helper (T(H)17) cells. T(H)17 cells comprise a CD4(+) T-cell subset that coordinates inflammatory responses in host defence but is pathogenic in autoimmunity. Batf(-/-) mice have normal T(H)1 and T(H)2 differentiation, but show a defect in T(H)17 differentiation, and are resistant to experimental autoimmune encephalomyelitis. Batf(-/-) T cells fail to induce known factors required for T(H)17 differentiation, such as RORgamma t (encoded by Rorc) and the cytokine IL21 (refs 14-17). Neither the addition of IL21 nor the overexpression of RORgamma t fully restores IL17 production in Batf(-/-) T cells. The Il17 promoter is BATF-responsive, and after T(H)17 differentiation, BATF binds conserved intergenic elements in the Il17a-Il17f locus and to the Il17, Il21 and Il22 (ref. 18) promoters. These results demonstrate that the AP-1 protein BATF has a critical role in T(H)17 differentiation.
Schraml
Barbara U
BU
Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Saint Louis, Missouri 63110, USA.
Hildner
Kai
K
Ise
Wataru
W
Lee
Wan-Ling
WL
Smith
Whitney A-E
WA
Solomon
Ben
B
Sahota
Gurmukh
G
Sim
Julia
J
Mukasa
Ryuta
R
Cemerski
Saso
S
Hatton
Robin D
RD
Stormo
Gary D
GD
Weaver
Casey T
CT
Russell
John H
JH
Murphy
Theresa L
TL
Murphy
Kenneth M
KM
D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D020381:Interleukin-17 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D007378:Interleukins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D008198:Lymph Nodes / Q000378:metabolism; D008297:Male; D051379:Mice; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D011401:Promoter Regions, Genetic / Q000235:genetics; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism; D011988:Receptors, Thyroid Hormone / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology* / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000098546:Interleukin-21
D050976:Basic-Leucine Zipper Transcription Factors; C431772:Batf protein, mouse; D020381:Interleukin-17; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D018168:Receptors, Retinoic Acid; D011988:Receptors, Thyroid Hormone; C539901:Rorc protein, mouse; D018808:Transcription Factor AP-1; D000098546:Interleukin-21