IL-27 and IL-12 oppose pro-inflammatory IL-23 in CD4+ T cells by inducing Blimp1

• Published in: Nature communications 2014-05, Vol.5 (1), p.3770-3770, Article 3770
• Main Authors: Heinemann, Christina, Heink, Sylvia, Petermann, Franziska, Vasanthakumar, Ajithkumar, Rothhammer, Veit, Doorduijn, Elien, Mitsdoerffer, Meike, Sie, Christopher, da Costa, Olivia Prazeres, Buch, Thorsten, Hemmer, Bernhard, Oukka, Mohamed, Kallies, Axel, Korn, Thomas
• Format: Article
• Language: English
• Subjects: 13/21; 13/31; 38/39; 631/250/127/1213; 631/250/256; 631/250/371; 631/250/516; 64/60; CD4-Positive T-Lymphocytes - immunology; Humanities and Social Sciences; Humans; Inflammation - prevention & control; Interferon-gamma - metabolism; Interleukin-12 - metabolism; Interleukin-23 - metabolism; Interleukins - metabolism; multidisciplinary; Positive Regulatory Domain I-Binding Factor 1; Repressor Proteins - metabolism; Science; Science (multidisciplinary)
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms4770

Central nervous system (CNS) autoimmunity is regulated by the balance of pro-inflammatory cytokines and IL-10. Here we identify the transcriptional regulator Blimp1 as crucial to induce IL-10 in inflammatory T helper cells. Pre-committed Th17 cells respond to IL-27 and IL-12 by upregulating Blimp1 and adopt a Tr-1-like phenotype characterized by IL-10 and IFN-γ production. Accordingly, Blimp1-deficient effector T cells fail to produce IL-10, and deficiency in Tr-1 cell function leads to uncontrolled Th17 cell-driven CNS pathology without the need to stabilize the Th17 phenotype with IL-23. IL-23 counteracts IL-27 and IL-12-mediated effects on Tr-1-development reinforcing the pro-inflammatory phenotype of Th17 cells. Thus, the balance of IL-23 vs IL-12/IL-27 signals into CD4 + effector T cells determines whether tissue inflammation is perpetuated or resolves. Autoimmune diseases are regulated by the balance between pro- and anti-inflammatory cytokines. Here, the authors show that the transcriptional regulator Blimp1 is induced in inflammatory T helper cells by the cytokines IL-27 and IL-12 to counteract pro-inflammatory IL-23 and promote resolution of tissue inflammation.