Activation and evolution of non-conventional T cells
Most T cells carry an αβ T cell antigen receptor (αβTCR) 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 αβTCR 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 αβ 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 (for a short general overview )
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 Butyrophilin 3A1 (BTN3A1), which is lacking in rodents. We could now show that besides BTN3A1 other molecules encoded by gene(s) on human chromosome 6 are essential for activation by PAg. Very recently we identified this molecule as BTN2A1 and could show together with our collaborators at Birmingham University (Willcox group) direct binding of BTN2A1 to a Vγ9-germ line encoded sequence of the TCR which resembles binding of superantigens to αβTCRs doi.org/10.1016/j.immuni.2020.02.014 . With this knowledge we continue our work on understanding activation of Vγ9Vδ2 T cell by PAg will work on 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. A special focus is the function of BTN3A1 which in human exists as a single molecule while in human three distinct BTN3A molecules need to cooperate for efficiently mediating PAg-activation https://www.pnas.org/content/117/12/6697 .
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.