Abstract
The T helper 9 (Th9) cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Here we show that, within this network, two interferon regulatory factors (IRF), IRF1 and IRF4, display opposing effects on Th9 differentiation. IRF4 dose-dependently promotes, whereas IRF1 inhibits, IL-9 production. Likewise, IRF1 inhibits IL-9 production by human Th9 cells. IRF1 counteracts IRF4-driven Il9 promoter activity, and IRF1 and IRF4 have opposing function on activating histone modifications, thus modulating RNA polymerase II recruitment. IRF1 occupancy correlates with decreased IRF4 abundance, suggesting an IRF1-IRF4-binding competition at the Il9 locus. Furthermore, IRF1 shapes Th9 cells with an interferon/Th1 gene signature. Consistently, IRF1 restricts the IL-9-dependent pathogenicity of Th9 cells in a mouse model of allergic asthma. Thus our study reveals that the molecular ratio between IRF4 and IRF1 balances Th9 fate, thus providing new possibilities for manipulation of Th9 differentiation.
Highlights
The T helper 9 (Th9) cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation
Neither the expression of several transcription factors involved in Th9 differentiation[10,12,16,18,21,22,23,24,25] including PU.[1], BATF, GATA-3 and T-bet nor the phosphorylation levels of STAT3 and STAT5 were significantly affected by IRF1-deficiency (Supplementary Fig. 1c–g)
We show that IRF1 limited IL-9 production downstream of IFNg/STAT1 signalling in mouse and human Th9 cells
Summary
The T helper 9 (Th9) cell transcriptional network is formed by an equilibrium of signals induced by cytokines and antigen presentation. Interferon (IFN)-g-producing Th1 cells express the master regulator T-bet and promote clearance of intracellular pathogens, whereas Th2 cells secreting interleukin (IL)-4, IL-5 and IL-13 are characterized by the master transcription factor GATA3 and contribute to immunity against helminths. 22) as well as TCR signalling[27] promote the expression of interferon regulatory factor 4 (IRF4), which is essential for Th9 differentiation[11]. IRF1 is expressed at low levels by most cell types and is induced by various stimuli, including IL-1, lipoploysaccharide, tumour necrosis factor and IFNs. In Th2 cells, IFN-g stimulation in combination with TCR signalling, strongly upregulates IRF1 expression leading to its increased binding to ISRE, inhibiting IL-4 production[39]. Considering these findings and that both IRF1 and IRF4 can be upregulated in Th9 cells[9,11], we speculated on a yet unknown interference between these two IRFs during Th9 differentiation
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