Interferon-regulatory factor 4 is essential for the developmental program of T helper 9 cells.
Interferon-regulatory factor 4 (IRF4) is essential for the development of T helper 2 (Th2) and Th17 cells. Herein, we report that IRF4 is also crucial for the development and function of an interleukin-9 (IL-9)-producing CD4(+) T cell subset designated Th9. IRF4-deficient CD4(+) T cells failed to develop into IL-9-producing Th9 cells, and IRF4-specific siRNA inhibited IL-9 production in wild-type CD4(+) T cells. Chromatin-immunoprecipitation (ChIP) analyses revealed direct IRF4 binding to the Il9 promoter in Th9 cells. In a Th9-dependent asthma model, neutralization of IL-9 substantially ameliorated asthma symptoms. The relevance of these findings is emphasized by the fact that the induction of IL-9 production also occurs in human CD4(+) T cells accompanied by the upregulation of IRF4. Our data clearly demonstrate the central function of IRF4 in the development of Th9 cells and underline the contribution of this T helper cell subset to the pathogenesis of asthma.
Staudt
Valérie
V
Institute for Immunology, University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
Bothur
Evita
E
Klein
Matthias
M
Lingnau
Karen
K
Reuter
Sebastian
S
Grebe
Nadine
N
Gerlitzki
Bastian
B
Hoffmann
Markus
M
Ulges
Alexander
A
Taube
Christian
C
Dehzad
Nina
N
Becker
Marc
M
Stassen
Michael
M
Steinborn
Andrea
A
Lohoff
Michael
M
Schild
Hansjörg
H
Schmitt
Edgar
E
Bopp
Tobias
T
D000818:Animals; D001249:Asthma / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation; D002478:Cells, Cultured; D006801:Humans; D050835:Interferon Regulatory Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016906:Interleukin-9 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D034741:RNA, Small Interfering / Q000235:genetics; D006377:T-Lymphocytes, Helper-Inducer / Q000166:cytology / Q000276:immunology*; D000099218:Interferon Regulatory Factor-4
D050835:Interferon Regulatory Factors; D016906:Interleukin-9; D034741:RNA, Small Interfering; D000099218:Interferon Regulatory Factor-4