Transcription factor IRF4 drives dendritic cells to promote Th2 differentiation

• Published in: Nature communications Vol. 4; no. 1; p. 2990
• Main Authors: Williams, Jesse W., Tjota, Melissa Y., Clay, Bryan S., Vander Lugt, Bryan, Bandukwala, Hozefa S., Hrusch, Cara L., Decker, Donna C., Blaine, Kelly M., Fixsen, Bethany R., Singh, Harinder, Sciammas, Roger, Sperling, Anne I.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.12.2013; Nature Publishing Group
• Subjects: 13/21; 38/61; 631/136/142; 631/250/1619/554/1898/1274; 631/250/2504/133; 631/45/612/822; 64/60; 96/106; 96/31; Animals; Asthma - metabolism; Bone Marrow Cells - cytology; Cell Differentiation; Dendritic Cells - cytology; Female; Gene Expression Regulation; Humanities and Social Sciences; Hypersensitivity, Immediate - metabolism; Immune response; Inflammation; Interferon Regulatory Factors - metabolism; Interleukin-10 - metabolism; Interleukins; Lung - metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mites; multidisciplinary; Oligonucleotide Array Sequence Analysis; Science; Science (multidisciplinary); Signal Transduction; Th2 Cells - cytology
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms3990

Atopic asthma is an inflammatory pulmonary disease associated with Th2 adaptive immune responses triggered by innocuous antigens. While dendritic cells (DCs) are known to shape the adaptive immune response, the mechanisms by which DCs promote Th2 differentiation remain elusive. Herein we demonstrate that Th2-promoting stimuli induce DC expression of IRF4. Mice with conditional deletion of Irf4 in DCs show a dramatic defect in Th2-type lung inflammation, yet retain the ability to elicit pulmonary Th1 antiviral responses. Using loss- and gain-of-function analysis, we demonstrate that Th2 differentiation is dependent on IRF4 expression in DCs. Finally, IRF4 directly targets and activates the Il-10 and Il-33 genes in DCs. Reconstitution with exogenous IL-10 and IL-33 recovers the ability of Irf4 -deficient DCs to promote Th2 differentiation. These findings reveal a regulatory module in DCs by which IRF4 modulates IL-10 and IL-33 cytokine production to specifically promote Th2 differentiation and inflammation. Asthma is often characterized by Th2-mediated inflammatory responses, which are initiated by lung dendritic cells. Here, Williams et al. demonstrate that dendritic cell expression of transcription factor IRF4 drives Th2 differentiation through IL-33 and IL-10 activation.