Investigating the function of gamma-delta T cells

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Gamma-delta T cells, B cells and alpha-beta T cells are lymphocytes that rearrange clonal antigen receptors during their development. These three lineages are conserved throughout evolution and across species. Gamma-delta T cells are frequent in mucosal tissues and in skin. However, their function is still only partially understood, not at least because there is no stringent loss-of-function experimental model suited to investigate the function of gamma-delta T cells. The phenotype of TCR delta chain knock-out mice is cloaked by unconventional gamma-delta T cell-like cells bearing alpha-beta T cell receptors that take over empty gamma-delta T cell niches. Furthermore, we recently showed that gamma-delta T cells are fully refractory to in vivo depletion by injection of monoclonal antibodies. In preliminary work, we have therefore generated a novel genetically modified mouse model to investigate the function of gamma-delta T cells in vivo. In these Tcrd-GDL mice, gamma-delta T cell-specific reporter fluorescence and luciferase expression will enable us to visualize gamma-delta T cells during immune responses in vivo. Furthermore, gamma-delta T cells of these mice express the human diphtheria toxin receptor. Because all other mouse cells do not express the transgenic toxin receptor, gamma-delta T cells can be conditionally and specifically ablated in vivo by injection of the toxin. We will employ the newly generated Tcrd-GDL mice to explore the function of gamma-delta T cells in vivo in experimental models for human disease. We will perform experimental fungal and bacterial infections and we will determine the role of gamma-delta T cells in models for psoriasis and wound healing. Furthermore, the Tcrd-GDL system is ideally suited and will be applied to investigate the development, differentiation and regenerative potential of pro-inflammatory effector gamma-delta T cell populations. Overall, the goal of this project is to reveal the specific biologic roles of gamma-delta T cells and to establish how far they might share redundant functions with other innate lymphocyte populations.