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. TThese 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.
|Xiao, Sheng; Yosef, Nir; Yang, Jianfei et al. (2014) Small-molecule ROR?t antagonists inhibit T helper 17 cell transcriptional network by divergent mechanisms. Immunity 40:477-89|
|Kofler, David M; Marson, Alexander; Dominguez-Villar, Margarita et al. (2014) Decreased RORC-dependent silencing of prostaglandin receptor EP2 induces autoimmune Th17 cells. J Clin Invest 124:2513-22|
|Lee, Youjin; Collins, Mary; Kuchroo, Vijay K (2014) Unexpected targets and triggers of autoimmunity. J Clin Immunol 34 Suppl 1:S56-60|
|Wu, Chuan; Pot, Caroline; Apetoh, Lionel et al. (2013) Metallothioneins negatively regulate IL-27-induced type 1 regulatory T-cell differentiation. Proc Natl Acad Sci U S A 110:7802-7|