„Constitutive autoreactivity of gamma-delta T cells as a beneficial mechanism of epidermal barier surveillane”
Project supported by the National Science Centre, Poland under the „OPUS 8” programme
Total cost: 1 287 623,00 PLN
Centre Contribution: 1 287 623,00 PLN
Duration: 30/09/2015 – 39/09/2018
Principal Investigator: dr Grzegorz Chodaczek
Autoreactive T cells are usually associated with debilitating autoimmune conditions, whereby the immune system recognizes and mounts a response against host tissues. Despite this prevailing view, I have shown that in the skin recognition of host-derived antigens by γδ T cells may be beneficial for the host; playing a critical role in maintenance of tissue homeostasis and regulation of wound healing. Novel and complementary use of static and intravital imaging techniques allowed demonstration that γδ T cells in healthy mouse skin are activated through continuous γδ T cell receptor (TCR) activation within immune synapse-like structures. These studies demonstrated that in contrast to the prevailing view, which assumes that γδ TCR only recognizes stress-induced antigens, it is likely that an endogenous γδ TCR ligand is expressed under normal conditions. Aside from TCR, skin γδ T cells regulate wound healing using NKG2D molecule, a receptor of NK cells, recognizing stress-induced proteins. In vitro studies have not unequivocally determined yet, which signaling pathway – TCR or NKG2D – is more important for effector functions of γδ T cells and stimulation of healing process. The analysis is further complicated by the fact that the endogenous γδ TCR ligand has not been identified yet. In the light of the discovery of constitutive synapses formed by skin γδ T cells it is not clear whether in vitro results are applicable to the in vivo situation. This proposed research project addresses aforementioned problems and seeks to understand the role of autoreactive TCR and the importance of γδ T cells in maintaining epidermal homeostasis. The general hypothesis is that synapses between γδ T cells and keratinocytes are the sites of constitutive transfer of intra- or extracellular material, which is either packed into cytoplasmic vesicles and released toward keratinocytes or internalized by lymphocytes. I also hypothesize that the trafficking of intracellular material in healthy and stressed tissue is differentially regulated depending on activation signals through γδ TCR or NKG2D receptor. Testing of these hypotheses will be performed to elucidate the role of the synapses. Previous studies have demonstrated accumulation of GM1 ganglioside in synaptic granules. Gangliosides were shown to induce differentiation of keratinocytes. This may suggest that synaptic effector functions are associated with ganglioside release and possibly stimulation of healing processes under stress conditions upon their secretion. This hypothesis is completely novel in the context of γδ T cells.