Regulatory T Cells and Th17 Cells in Autoimmune Brain Inflammation

• Applicant: Professor Dr. Ari Waisman
• Subject Area: Molecular and Cellular Neurology and Neuropathology ; Immunology
• Term: from 2014 to 2017
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 246815631

Immune responses are always a balance between effector and regulatory cells, which determine the extent and duration of the response. Two important cell types involved in immune responses in general, and autoimmune responses in particular, are regulatory (Tregs) and IL-17-producing CD4+ T cells (Th17). Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), and is modeled in mice by a disease termed experimental autoimmune encephalomyelitis (EAE). It was shown previously that depletion of Treg cells results in excessive EAE, and on the other hand, it was shown that Th17 cells are critical for the development of this disease. We generated a new mouse strain that allow the ablation and manipulation of Th17 cells. Using these mice we were able to mark and follow Th17 cells in vivo, and show their plasticity and transient nature. Further, we developed new mouse strains that allowed us to test directly the function of IL-17A in autoimmunity. We could show that although IL-17A is dispensable for the development of EAE, it was sufficient for the trigger of psoriasis-like disease in mice. To study the need for RORgt and IRF-4 for the development and stability of Th17 cells, we have obtained mice that allow for the conditional deletion of these two genes. These mice were crossed to mice that express the Cre recombinase in in all T cells or specifically in Th17 cells. We have found that mice lacking IRF-4 specifically in T cells are resistant to EAE induction, and further, that they do not develop Th17 cells. Finally, we have generated mice that overexpress the NF-kB family protein Bcl-3 in T cells. Bcl-3 is a transcriptional transactivator that binds p50/p52 heterodimers and homodimers. Our overexpressing mice show defects in T cell activation and spontaneous development of colitis.In the current application we plan to study the molecular requirements for the development and maintenance of Th17 cells. We will study how the deletion of RORgt and IRF-4 in all T cells or specifically in Th17 cells impact on the pathogenicity of these cells and their plasticity towards Th1 or Treg cells. This will be done using the conditional KO mice for these two transcriptional factors crossed to mice that express the Cre-recombinase in all T cells or specifically in Th17 cells. We will use mice that allow cell fate marking and follow the fate of Th17 cells once they lose the expression of these transcription factors, in a mouse model of CNS inflammation. Further more, we will use the above-mentioned new models to manipulate Bcl-3 expression in T cells and study the importance of this molecule for the development of Th17 and Treg cells. For that, we will overexpress Bcl-3 in all T cells or specifically in Th17 cells and follow the course of EAE in these mice. Together, these studies will help us to better understand the pathogenicity of Th17 cells and their lineage relationship with Th1 and Treg cells.

• DFG Programme: Research Grants