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

Abstract

T lymphocytes comprise cells expressing either an αβ or a γδ TCR. The riddle how αβ 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 γδ TCRs are still baffling the scientific community. It is clear that activation of γδ 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 γδ TCR. However, for most γδ 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 γδ 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 γδ TCR and have made it conceivable to revise the current knowledge and contextualize the new findings.

Keywords: antigen recognition; gamma-delta TCR; ligands.

Fig. 1

Mechanisms for the discrimination of health and stress conditions via the γδ TCR. a The putative γδ TCR ligand might be differentially expressed depending on the stress level of the cell. In the case of stress-induced antigens such as Annexin A2 or MICA/MICB this would mean an upregulation whereas BTNL molecules might be downregulated allowing for γδ TCR activation via the CDR3. b Co-stimulatory molecules such as CD27 or JAML might be required for full activation of the γδ TCR and their upregulation might be triggered by stress conditions. c Changes in the conformation of the ligand might increase the accessibility of a particular γδ TCR binding domain. BTN3A1 for example undergoes conformational changes upon p-Ag binding. d Multimerization or monomerization of the respective ligand can be triggers for γδ TCR as in the case of the HLA-molecule A*24:02. e Glycosylation patterns are modified upon infections or tumor development. These changes in post-translational modifications might lead to different outcomes of γδ TCR interaction with the same ligand with different glycan residues on the extracellular domain