PhD SCIENCE REPORT EWA SKOTNICKA: Interplay between Foxp3+ regulatory T cells and CD83+ dendritic cells / soluble CD83

EWA SKOTNICKA

Peripheral T cell tolerance, mediated by antigen-presenting steady state dendritic cells, is thought to significantly contribute to the prevention of autoimmunity. We set out to analyze the involvement of FoxP3+ regulatory T-cells, which are known to be important for maintenance of self-tolerance, in dendritic cell-induced peripheral tolerance of T-cells.
Most autoreactive T cells are deleted in the thymus. Peripheral autoreactive T cells are controlled by peripheral tolerance, which acts through unresponsiveness/anergy, regulation/suppression and deletion. CD4+CD25+FoxP3+Treg were characterized by their immunosuppressive properties and comprise 10-15% of peripheral CD4+T-cells in mice. Loss-of-function mutations of FoxP3 in the result in autoimmune disease in humans and mice and depletion of Tregs causes fatal autoimmunity. Furthermore, FoxP3+Treg regulate inflammatory disorders such as colitis and immune responses to transplants, tumors and infectious agents. The forkhead box transcription factor FoxP3 is crucially involved in the function of Treg and is the best marker for Treg. In the lab of T.S. the FoxP3 gene locus was used to generate BAC transgenic (DEREG) mice allowing for tracking and inducible depletion of Tregs. In the laboratory of T.S. tolerogenic DC subpopulations are characterized in further detail. The PhD student in the laboratory involved in the collaborative project, Ewa Skotnicka, was supposed to test different DC-subsets cultivated in vitro and isolated ex vivo in regard to their capacity to induce Tregs. The advantage of the DEREG system is that for the first time antigen-specific induced Tregs (from DEREG*Rag-/-OT-II mice) can be differentiated from natural Tregs. Another intriguing observation from our own lab and the lab of others is the existence of TLRs on Tregs. The DC-Thera student was supposed to test the influence of TLR ligands for the induction of Tregs in vitro and in vivo. For the last year the PhD student refused to perform the suggested in vitro experiments. Despite several formal instructions, no significant progress was made. As a consequence, we decided to lay off the student by the end of the year. The joint collaborative project between A.S. and T.S. will be continued with own funds. T.S. has accepted a position as full professor (W3, director, institute for infection immunology) in Hanover. T.S. is currently applying for a Position as DC-Thera associated partner. The DEREG mouse system was successfully transferred to the laboratory of A.S. In the lab of A.S. the animal model for human Multiple Sklerosis i.e. the experimental autoimmune encephalitis (EAE) has been established and initial experiments have been already performed in DEREG mice. In the future we will investigate the role of Tregs during the course of the disease and for the treatment of EAE-associated paralysis in vivo. In the long term this could lead to the establishment of new therapeutic strategies.

created over 14 years ago (16 April 2010)    last modified over 13 years ago (28 September 2011)   [ RDF ]   [ RelFinder ]