IRF8-dependent molecular complexes control the Th9 transcriptional program

Etienne Humblin, Marion Thibaudin, Fanny Chalmin, Valentin Derangère, Emeric Limagne, Corentin Richard, Richard A. Flavell, Sandy Chevrier, Sylvain Ladoire, Hélène Berger, Romain Boidot, Lionel Apetoh, Frédérique Végran () and François Ghiringhelli ()
Additional contact information
Etienne Humblin: Univ. Bourgogne Franche-Comté
Marion Thibaudin: Univ. Bourgogne Franche-Comté
Fanny Chalmin: Centre de Recherche INSERM LNC-UMR1231
Valentin Derangère: Univ. Bourgogne Franche-Comté
Emeric Limagne: Centre de Recherche INSERM LNC-UMR1231
Corentin Richard: Univ. Bourgogne Franche-Comté
Richard A. Flavell: School of Medicine
Sandy Chevrier: Centre Georges-François Leclerc
Sylvain Ladoire: Univ. Bourgogne Franche-Comté
Hélène Berger: Univ. Bourgogne Franche-Comté
Romain Boidot: Centre de Recherche INSERM LNC-UMR1231
Lionel Apetoh: Centre de Recherche INSERM LNC-UMR1231
Frédérique Végran: Centre de Recherche INSERM LNC-UMR1231
François Ghiringhelli: Univ. Bourgogne Franche-Comté

Nature Communications, 2017, vol. 8, issue 1, 1-13

Abstract: Abstract Interferon regulatory factors (IRF) have critical functions in lymphoid development and in immune response regulation. Although many studies have described the function of IRF4 in CD4+ T cells, few have focused on the IRF4 homologue, IRF8. Here, we show that IRF8 is required for Th9 differentiation in vitro and in vivo. IRF8 functions through a transcription factor complex consisting of IRF8, IRF4, PU.1 and BATF, which binds to DNA and boosts Il9 transcription. By contrast, IRF8 deficiency promotes the expression of other genes such as Il4, as IRF8 dimerises with the transcriptional repressor ETV6 and inhibits Il4 expression. In vivo, IRF8 is essential for the anti-tumour effects of Th9 cells in mouse melanoma models. Our results show that IRF8 complexes boost the Th9 program and repress Il4 expression to modulate Th9 cell differentiation, thereby implicating IRF8 as a potential therapeutic target to affect Th9 responses in cancer therapy.

Date: 2017
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DOI: 10.1038/s41467-017-01070-w

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