Constitutive Autoreactivity of Gamma Delta T Cells as a Beneficial Mechanism of Epidermal Barrier Control – OPUS_TGD

Autoreactive T lymphocytes are typically associated with debilitating autoimmune diseases, in which the immune system attacks the body’s own tissues. However, the applicant demonstrated—using cutaneous γδ T cells—that autoreactivity can actually be beneficial and play a critical role in maintaining tissue homeostasis and regulating wound healing (Chodaczek et al., Nature Immunology, 2012).

Through an innovative combination of static and intravital microscopy techniques, it was shown that γδ T lymphocytes in the healthy mouse skin are constitutively activated due to continuous stimulation of the γδ T-cell receptor (TCR γδ) within immunological synapses. Contrary to the prevailing view that TCR γδ recognizes undefined stress-induced antigens, these findings suggest the presence of a ligand for TCR γδ that exists even in healthy tissue.

In controlling wound healing, cutaneous γδ T cells utilize not only TCR but also NKG2D, a receptor characteristic of NK cells, which recognizes proteins induced by tissue injury. However, in vitro studies have not definitively established which signaling pathway—TCR or NKG2D—plays a greater role in the effector functions of γδ T cells and their ability to stimulate wound repair. The analysis is complicated by the fact that the natural ligand for the skin TCR γδ receptor remains unidentified.

Given the unexpected discovery of constitutive γδ T-cell synapses, it is still unclear whether in vitro findings accurately reflect the in vivo situation. The proposed project was designed to address these unresolved questions and aims to elucidate the role of autoreactive TCR γδ and the significance of cutaneous γδ T cells in maintaining epidermal homeostasis.

The central research hypothesis assumes that constitutive synapses serve as sites of intracellular or extracellular material transfer, with such material—stored in cytoplasmic granules—either secreted toward keratinocytes or internalized by the lymphocyte. It is further hypothesized that the dynamics of intracellular transport differ between healthy and stressed tissue, depending on the activation signal delivered by either TCR γδ or NKG2D.

The research tasks described in this project are designed to test these hypotheses. Previous studies revealed an accumulation of GM1 ganglioside-containing vesicles within the synapses. Since gangliosides are known to induce keratinocyte differentiation, it is hypothesized that γδ T cells release these vesicles to promote wound healing. This concept is entirely novel in the context of γδ T-cell biology.