EAE is induced because of inflammation of central nervous system (CNS) primarily caused by autoreactive CD4+ T cells. It is well documented that myelin-specific T cells, especially TH1 cells and more recently TH17 cells, are important in the initiation of tissue inflammation in EAE. We have demonstrated that IL-27, a member of the IL-12 family of cytokines, directly suppresses the induction of TH17 cells and generates regulatory IL-10-producing type 1 regulatory T (Tr1) cells. However, the mechanism by which IL-27 mediates inhibition of TH17 cells and promotion of Tr1cells is not well understood. In vivo administration of IL-27 suppresses the development of Th17 cells and EAE. Our preliminary data suggests that IL-27 controls tissue inflammation in EAE by two different but interlinked mechanisms: 1, by inducing the expression of IL-12R?2, and therefore inhibiting the generation of Th17 cells in an IL-12 dependent manner;2, by enhancing the expression of two transcription factors, AhR and c-Maf, that generate Tr1 cells. In this project, we will molecularly define the mechanism by which IL-27 regulates tissue inflammation in EAE by studying the following specific aims: 1) Mechanism by which IL-27 inhibits generation of Th17 cells by studying whether induction of IL-12R?2 chain by IL-27 not only suppresses IL-23R expression but also makes Th17 cells highly responsive to IL-12 and make them plastic to produce IFN-y;2) How IL-27 generates Tr1 cells by studying the role of transcription factors AhR and cMaf and their mutual association in differentiating Tr1 cells. These studies will be accomplished by using AhR, cMaf and AhR x cMaf double """"""""knock-out"""""""" mice;3) Study interplay between Th17 and Tri in the development of tissue inflammation in EAE, using IL-17, IL-10 and FoxP3 reporter mice. These studies will provide a mechanistic basis of how IL-27 suppresses autoimmunity and tissue inflammation in the CNS.
These Studies will provide insight into the mechanisms by which IL-27 suppresses autoimmunity. IFN-?, a first line therapy used in the treatment of MS patients, has been shown to induce IL-27 from innate immune system thus making these studies highly relevant for studying the regulation of autoimmunity and tissue inflammation in the CNS.
|Aschenbrenner, Dominik; Foglierini, Mathilde; Jarrossay, David et al. (2018) An immunoregulatory and tissue-residency program modulated by c-MAF in human TH17 cells. Nat Immunol 19:1126-1136|
|Meyer Zu Horste, Gerd; Przybylski, Dariusz; Schramm, Markus A et al. (2018) Fas Promotes T Helper 17 Cell Differentiation and Inhibits T Helper 1 Cell Development by Binding and Sequestering Transcription Factor STAT1. Immunity 48:556-569.e7|
|Joller, Nicole; Kuchroo, Vijay K (2017) Tim-3, Lag-3, and TIGIT. Curr Top Microbiol Immunol 410:127-156|
|Karwacz, Katarzyna; Miraldi, Emily R; Pokrovskii, Maria et al. (2017) Critical role of IRF1 and BATF in forming chromatin landscape during type 1 regulatory cell differentiation. Nat Immunol 18:412-421|
|Hu, Dan; Notarbartolo, Samuele; Croonenborghs, Tom et al. (2017) Transcriptional signature of human pro-inflammatory TH17 cells identifies reduced IL10 gene expression in multiple sclerosis. Nat Commun 8:1600|
|Chihara, Norio; Madi, Asaf; Karwacz, Katarzyna et al. (2016) Differentiation and Characterization of Tr1 Cells. Curr Protoc Immunol 113:3.27.1-3.27.10|
|Anderson, Ana C; Joller, Nicole; Kuchroo, Vijay K (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors with Specialized Functions in Immune Regulation. Immunity 44:989-1004|
|Meyer Zu Horste, Gerd; Wu, Chuan; Wang, Chao et al. (2016) RBPJ Controls Development of Pathogenic Th17 Cells by Regulating IL-23 Receptor Expression. Cell Rep 16:392-404|
|Mayo, Lior; Cunha, Andre Pires Da; Madi, Asaf et al. (2016) IL-10-dependent Tr1 cells attenuate astrocyte activation and ameliorate chronic central nervous system inflammation. Brain 139:1939-57|
|Gaublomme, Jellert T; Yosef, Nir; Lee, Youjin et al. (2015) Single-Cell Genomics Unveils Critical Regulators of Th17 Cell Pathogenicity. Cell 163:1400-12|
Showing the most recent 10 out of 18 publications