Molecular mechanisms that dictate the differentiation of Th17 cells in autoimmunity

• Applicant: Dr. Rebekka Duhen
• Subject Area: Immunology
• Term: from 2012 to 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 216601213

Upon activation with antigen in a specific cytokine environment, CD4+ T helper (Th) cells can differentiate in Th1, Th2 or Th17 subsets, characterized by distinct effector functions and the production of specific effector cytokines. Th17 cells secrete IL-17A, IL-17F, IL-21 and IL-22 and have been implicated along with Th1 cells, secreting mainly IFN-g, in the pathogenesis of autoimmune diseases including multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). In addition to its effects on the expansion of Th17 cells, we determined that IL-23 induces a population of cells co-expressing IL-17 and IFN-g. These cells have been described to infiltrate the target tissues in several autoimmune diseases. However, their function is unknown. In aim 1 of my proposal I will test the hypothesis that those double producing cells are highly pathogenic and critical in promoting EAE. A dual reporter mouse (IFN-g Thy1.1 / IL-17A GFP) will serve as a unique tool in our study to address this question. In aim 2, I will determine which transcription factor(s) are responsible for the IL-23 driven IFN-g production in IL-17+ IFN-g+ T cells. After having excluded the involvement of Th1 associated transcription factors, our main candidate is the aryl hydrocarbon receptor (AhR) , a transcription factor preferentially expressed in Th17 cells. It is known to favor IL-22 expression and is enhanced by IL-23. In a complementary approach, we will perform DNase Chip to identify other possible transcription factor binding sites in the IFN-g locus of cells producing IL-17 and IFN-g. Together these experiments will provide valuable information on the genetic signature of IL-17+ IFN-g+ cells and aid to define the role of IL-17+IFN-g+ cells in an autoimmune setting such as EAE.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Estelle Bettelli, Ph.D.