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Published on: October 6, 2019
IRF8-dependent molecular complexes control the Th9 transcriptional program
Etienne Humblin1,2, Marion Thibaudin1,2, Fanny Chalmin2
1Univ. Bourgogne Franche-Comté, F-21000, Dijon, France.
Insights
Interferon regulatory factor 8 (IRF8) is crucial for Th9 cell differentiation and function. This study reveals IRF8
Area of Science:
- Immunology
- Molecular Biology
- Cell Biology
Background:
- Interferon regulatory factors (IRFs) are key regulators of immune responses.
- IRF4's role in CD4+ T cells is well-studied, but IRF8's function remains less understood.
Purpose of the Study:
- To investigate the role of IRF8 in Th9 cell differentiation and function.
- To elucidate the molecular mechanisms by which IRF8 regulates Th9 cell development.
Main Methods:
- In vitro differentiation of Th9 cells.
- In vivo studies using mouse models.
- Analysis of transcription factor complexes and gene expression (Il9, Il4).
Main Results:
- IRF8 is essential for Th9 differentiation both in vitro and in vivo.
- IRF8 forms a complex with IRF4, PU.1, and BATF to enhance Il9 transcription.
- IRF8, in complex with ETV6, represses Il4 expression.
- IRF8-dependent Th9 cells exhibit anti-tumour effects in melanoma models.
Conclusions:
- IRF8 plays a critical role in promoting the Th9 cell program and suppressing Il4 expression.
- IRF8 modulates Th9 cell differentiation through specific transcription factor complexes.
- IRF8 represents a potential therapeutic target for enhancing Th9 responses in cancer therapy.
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.
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