Mechanism of interleukin-27 mediated inhibition of Th17 cells in experimental autoimmune encephalomyelitis.

• Applicant: Privatdozent Dr. Gerd Meyer zu Hörste
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 218475164

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system and experimental autoimmune encephalomyelitis (EAE) serves as its most commonly used animal model. The interleukin (IL)-17 producing T helper cell subset (Th17) induces EAE and data indicate a central relevance in MS and other autoimmune diseases. The differentiation of Th17 cells is regulated by the cytokines transforming growth factor (TGF)-ý and IL-6, while IL-23 is essential for their stabilization. Th17 cell differentiation and EAE manifestation can be controlled by the anti-inflammatory cytokine IL-27, although the exact underlying cellular mechanisms remain unknown. Here, we will experimentally approach these mechanisms and study whether altered Th17 differentiation also determines autoimmunity in peripheral nerves.The IL-23 receptor (IL-23R) shares a common subunit - termed IL-12Rý1 - with the IL-12 receptor (IL-12R). Preliminary experiments have demonstrated that the IL-12 specific receptor subunit is required for the anti-inflammatory effect of IL-27. We propose that IL-27 inhibits pro-inflammatory IL-23R signaling by inducing IL-12R signaling and regulates both specific receptor subunits in a reciprocal fashion. We will study this proposed balance between IL-12R and IL-23R signaling using reporter mice for the receptors of all cytokines involved. We will study if IL-12R modulates the generation of Th17 cells by regulating expression of the IL-23R indicating interaction of both signaling pathways. We will analyze if IL-27 inhibits Th17 cells in EAE by regulating expression of the IL-23R and if IL-27 modulates the stability of Th17 cells during the course of EAE. We will perform a transcriptional analysis to further identify anti-inflammatory mechanisms of IL-27. The intended project will further clarify how IL-27 modulates Th17 cell function, which constitutes a potential target for the future treatment of autoimmune disorders.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Vijay Kuchroo, Ph.D.