Activation and evolution of non-conventional T cells
Most T cells carry an ab T cell antigen receptor (abTCR) and recognize complexes of (foreign) peptides and polymorphic MHC class I or II molecules. Like most B cells they are part of the adaptive immune system. Quite differently, 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 research focus lies on mechanisms and evolution of their antigen-recognition and the activation of such cells.
Certain populations of non-conventional T cells (iNKT cells, MAIT cells) carry an abTCR but recognize complexes of (glyco)lipids and folic acid metabolites with non-polymorphic MHC class I like molecules. Other non-conventional T cells are γδ T cells. These cells are phylogenetically as old as ab T cells or B cells.
A peculiarity of many non-conventional T cells is that use of their TCR genes often correlates with the cell function and localization. That is why they are often named after these genes such as in case of Vγ9Vδ2 T cells, our current research focus.
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.
A description of the work of the years 2014/2015 can be found on our reports for the Zentrum für Infektionsforschung (ZINF), for the years 2016/2017 see pages 82/83https://www.uni-wuerzburg.de/zinf/startseite/