Treg-specific IL-27Rα deletion uncovers a key role for IL-27 in Treg function to control autoimmunity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 38; pp. 10190 - 10195
• Main Authors: Do, Jeongsu, Kim, Dongkyun, Kim, Sohee, Valentin-Torres, Alice, Dvorina, Nina, Jang, Eunjung, Nagarajavel, Vivekananthan, DeSilva, Tara M., Li, Xiaoxia, Ting, Angela H., Vignali, Dario A. A., Stohlman, Stephen A., Baldwin, William M., Min, Booki
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 19.09.2017
• Subjects: Accumulation; Animal tissues; Animals; Autoimmune Diseases - drug therapy; Autoimmune Diseases - immunology; Autoimmunity; Biological Sciences; CD4 antigen; Cell fate; Central nervous system; Central Nervous System - immunology; Clonal deletion; Control stability; Drug Evaluation, Preclinical; Encephalomyelitis - drug therapy; Encephalomyelitis - immunology; Experimental allergic encephalomyelitis; Fate maps; Forkhead Transcription Factors - metabolism; Foxp3 protein; Inflammation; Interleukin 10; Interleukin 17; Interleukin 27; Interleukins - metabolism; Interleukins - therapeutic use; Lymphocytes; Lymphocytes T; Mice; Mice, Transgenic; Nervous system; Receptors, Cytokine - genetics; Receptors, Cytokine - metabolism; Receptors, Interleukin; Rodents; Studies; T-Lymphocytes, Regulatory - metabolism; IL-27; Foxp3+ regulatory T cells; autoimmunity; Tr1 cells
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1703100114

Dysregulated Foxp3⁺ Treg functions result in uncontrolled immune activation and autoimmunity. Therefore, identifying cellular factors modulating Treg functions is an area of great importance. Here, using Treg-specific Il27ra −/− mice, we report that IL-27 signaling in Foxp3⁺ Tregs is essential for Tregs to control autoimmune inflammation in the central nervous system (CNS). Following experimental autoimmune encephalomyelitis (EAE) induction, Treg-specific Il27ra −/− mice develop more severe EAE. Consistent with the severe disease, the numbers of IFNγ- and IL-17–producing CD4 T cells infiltrating the CNS tissues are greater in these mice. Treg accumulation in the inflamed CNS tissues is not affected by the lack of IL-27 signaling in Tregs, suggesting a functional defect of Il27ra −/− Tregs. IL-10 production by conventional CD4 T cells and their CNS accumulation are rather elevated in Treg-specific Il27ra −/− mice. Analysis with Treg fate-mapping reporter mice further demonstrates that IL-27 signaling in Tregs may control stability of Foxp3 expression. Finally, systemic administration of recombinant IL-27 in Treg-specific Il27ra −/− mice fails to ameliorate the disease even in the presence of IL-27–responsive conventional CD4 T cells. These findings uncover a previously unknown role of IL-27 in regulating Treg function to control autoimmune inflammation.