Activation and evolution of non-conventional T cells
Non-conventional T cells bridge adaptive and innate immune system. Their T cell antigen receptors (TCR) do not recognize pathogen-specific antigens but disease associated molecular patterns. Our focus lies on mechanisms and evolution of their antigen-recognition and the activation of such cells.
Evolution, antigen recognition and activation of Vγ9Vδ2 T cells
1-5% of blood cells bear eponymous Vγ9Vδ2 T cell antigen receptors (TCR). These TCR recognize so called phosphoantigens (PAg) which are phosphorylated metabolites of isoprenoidsynthesis. Vγ9Vδ2 T cells eliminate tumor cells and expand to up to 50% of blood T cells in infections with pathogens producing the PAg HMBPP. Important HMBPP producers are Plasmodium spp. (Malaria) or Mycobacteria spp. (Tuberculosis, Lepra). So far Vγ9Vδ2 T cells have been considered as being primate specific and consequently there is no small animal model available. One of the molecules essential for activation is BTN3A1, which is lacking in rodents. We could now show that besides BTN3A1 other molecules encoded by genes on human chromosome 6 are essential for activation by PAg. Currently, we try to identify these genes. Their identification will not only help in a better understanding of Vγ9Vδ2 T cell function but is also crucial for the generation of transgenic mice with a functional Vγ9Vδ2 T cell compartment.
We also identified the camelid species alpaca (Vicugna pacos) to bear functional Vγ9Vδ2 TCR and BTN3A genes and investigate the possibility of existence PAg-specific Vγ9Vδ2 T cells in this species. Identification of such cells in a rather distantly related species can be expected to help in identifying common themes of Vγ9Vδ2 T cell physiology.
Finally, we are continuing our studies on the mechanistic basis of activation of Vγ9Vδ2 T cells with respect to BTN3A isoforms and modulators of isoprenoid synthesis such as clinically approved aminobisphosphonates aiming to exploit this knowledge for Vγ9Vδ2 T cell based tumor therapy.
CD1d, iNKT cells and non-conventional MHC class II molecules
iNKT cells recognize glycolipid antigens presented by non-polymorphic MHC class I molecules. We performed a detailed analysis of the CD1d/iNKT cell system in rat and cotton rat with the help of newly generated CD1d oligomers which allowed direct identification of iNKT cells in both species. This analysis included mutagenesis of iNKT TCR and identification of the HV4 region of TCR α-chain as modulator of binding of the iNKT TCR to CD1d antigen complexes. Also characterized were parameters of loading CD1d of different species with glycolipids. Finally, studies on two highly conserved MHC class II molecules of mouse (H2-Eb2) and rat (RTDb2) were largely completed. Current focus lies on the collaboration with Stefan Niewiesk (Ohio State University, Columbus) on the analysis of iNKT cells in the cotton rat which provides an important model for human virus infections (Measles, RSV).
For a description of the work of the last years please download the respective page of the report of the ZINF.