Ligand recognition by the γδ TCR and discrimination between homeostasis and stress conditions

T lymphocytes comprise cells expressing either an alpha beta or a gamma delta TCR. The riddle how alpha beta TCRs are triggered by specific peptides presented in the context of MHC was elucidated some time ago. In contrast, the mechanisms that underlie antigen recognition by gamma delta TCRs are still baffling the scientific community. It is clear that activation of gamma delta TCRs does not necessarily depend on MHC antigen presentation. To date, diverse and largely host-cell-derived molecules have been identified as cognate antigens for the gamma delta TCR. However, for most gamma delta TCRs, the activating ligand is still unknown and many open questions with regard to physiological relevance and generalizable concepts remain. Especially the question of how gamma delta T cells can distinguish homeostatic from stress conditions via their TCR remains largely unresolved. Recent discoveries in the field might have paved the way towards a better understanding of antigen recognition by the gamma delta TCR and have made it conceivable to revise the current knowledge and contextualize the new findings.