Kurzfassung

Immune responses are always a balance between effector and regulatory cells, which deter-mine 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 T cells (Th17). Previously, it was shown that depletion of Treg cells results in excessive autoimmune responses. On the other hand, it was shown that Th17 cells are in-volved in the development of autoimmune...Immune responses are always a balance between effector and regulatory cells, which deter-mine 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 T cells (Th17). Previously, it was shown that depletion of Treg cells results in excessive autoimmune responses. On the other hand, it was shown that Th17 cells are in-volved in the development of autoimmune inflammatory responses in the central nervous sys-tem (CNS) in a mechanism that is not well understood. We generated new mouse strains 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 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 RORγt and IRF-4 in the devel-opment and stability of Th17 cells, we have obtained mice that allow for the conditional dele-tion of these two genes. These mice were crossed to mice that express the Cre recombinase in either Th17 cells, or under the CD4 or Lck promoters. We have found that mice lacking IRF-4 specifically in T cells are resistant to EAE induction, and further, that they do not devel-op Th17 cells.
In the next funding period we plan to continue and analyse the development of Th1 and Th17 cells and use a new set of mice obtained in the lab to study the requirement for IL-1 in this
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process. Further, we have generated mice that allow for the conditional deletion of the SU-MO-removing enzyme SENP1 and are in the process of generating conditional mice to delete SENP2. We plan to cross these mice to the CD4-Cre line to study the involvement of SUMO in the differentiation of T cells. Finally, we have generated mice that overexpress the NF-κB family protein Bcl-3 in T cells. Bcl-3 is a transcriptional transactivator that binds p50/p52 het-erodimers and homodimers. Our overexpressing mice show defects in T cell activation and spontaneous development of colitis. We plan to study these T cells to understand how Bcl-3 affects T cell function and differentiation.» weiterlesen» einklappen