The role of CD28 and interleukin-2-mediated signals in the generation, maintenance and activation of regulatory T-cells

• Antragsteller: Professor Dr. Thomas Hünig
• Fachliche Zuordnung: Immunologie
• Förderung: Förderung von 2005 bis 2010
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 19657246

Some CD28-specific monoclonal antibodies (mAbs) have the surprising property that they activate T-cells without the need for TCR ligation. We have previously compared such ¿superagonistic and conventional CD28-specific mAbs with regard to binding specificity and signalling properties in the rat and human systems. Furthermore, we observed dramatic effects after in vivo application of CD28 superagonists to rats with regard to the induction of regulatory T-cells and polyclonal T-cell expansion. We have now succeeded in generating both superagonistic and conventional (in vivo: blocking) mouse-CD28 specific mAbs which faithfully reproduce all effects previously observed in rats. These new reagents will allow us to harness the genetic tools of the mouse system for an in depth mechanistic analysis of the impact of CD28 superagonist mediated signals on the generation, survival and function of conventional and regulatory T-cells. Specifically, CD28 signals acting in cis will be dissociated from CD28-dependent production of IL-2 (the major survival factor for regulatory T-cells). T-cell generation will be studied in fetal thymic organ culture (FTOC) whereas fluorescent dye dilution of transferred T-cells will be used to study survival and expansion in vivo. Mice deficient in CD28 or certain intracellular signalling motifs of CD28 and supposed downstream signaling components will be used to study the role and transmission of CD28 signals, and mice lacking IL-2 or the light chain of the IL-2 receptor, CD25, will be used to investigate the importance of auto- and paracrine IL-2. Since deficiency in regulatory T-cells is known to promote autoimmune diseases, we will artificially deplete this subset and test the ability of CD28 superagonists to restore it numerically and functionally. Finally, we will follow up our observation that among ¿natural regulatory T-cells, only a small subset produces IL-10. We plan to investigate whether this is a stable phenotype and whether additional genes relevant for suppression are co-regulated with IL-10.

• DFG-Verfahren: Sachbeihilfen