The project seeks to reveal the molecular mechanisms controlling the pathogenicity of lymphocytes in multiple sclerosis. For this, mRNA-Seq and a Cre/loxP-based mouse model will be used to analyse the impact of the Th1-associated transcription factor T-bet on the encephalitogenicity of IL-17-producing cells in EAE.

• Applicant: Dr. Verena Brucklacher-Waldert
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: from 2011 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 199830834

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. The pathogenesis of MS requires the involvement of self-reactive CD4+ T effector cells, such as T helper (Th)1 lymphocytes, characterised by the production of interferon-gamma, and the recently discovered Th17 cells, named according to their production of the cytokine interleukin (IL)-17. Although great progress has been made in recent years with respect to the differentiation requirements and functional characteristics of these T cells, the molecular basis determining their pathogenicity remains ill defined. A profound and in depth knowledge of the mechanisms controlling the pathogenicity of lymphocytes is essential for the path towards effective therapeutic intervention in autoimmune disorders. Therefore, the proposed project aims to provide insights into molecular mechanisms that shape lymphocytes with an encephalitogenic potential and will increase the understanding of factors involved in phenotypic differentiation and specialisation. The focus of this proposal is on the transcription factor T-bet, which controls multiple aspects of Th1 cell biology during inflammatory responses. Interestingly, T-bet is also expressed in Th17 cells, suggesting an additional role in Th-biology. The impact of the Th1-associated transcription factor T-bet on the encephalitogenicity of IL-17-producing cells will be investigated using experimental autoimmune encephalitomyelitis (EAE), an animal model for MS, with two approaches. First, a Cre/loxP-based reporter mouse model with an IL-17-specific deletion of T-bet will reveal the function of T-bet in IL-17-producing cells in vivo. Second, the high-throughput sequencing technology mRNA-sequencing (RNA-Seq) will enable an in-depth study of the molecular mechanisms initiated by T-bet in Th17 cells.

• DFG Programme: Research Fellowships
• International Connection: United Kingdom
• Host: Marc Veldhoen, Ph.D.