Human γδ T cell sensing of AMPK-dependent metabolic tumor reprogramming through TCR recognition of EphA2

Human gamma delta T cells contribute to tissue homeostasis and participate in epithelial stress surveillance through mechanisms that are not well understood. Here, we identified ephrin type-A receptor 2 (EphA2) as a stress antigen recognized by a human V gamma 9V delta 1 TCR. EphA2 is recognized coordinately by ephrin A to enable gamma delta TCR activation. We identified a putative TCR binding site on the ligand-binding domain of EphA2 that was distinct from the ephrin A binding site. Expression of EphA2 was up-regulated upon AMP-activated protein kinase (AMPK)-dependent metabolic reprogramming of cancer cells, and coexpression of EphA2 and active AMPK in tumors was associated with higher CD3 T cell infiltration in human colorectal cancer tissue. These results highlight the potential of the human gamma delta TCR to cooperate with a co-receptor to recognize non-MHC-encoded proteins as signals of cellular dysregulation, potentially allowing gamma delta T cells to sense metabolic energy changes associated with either viral infection or cancer.

Automated summary

In this study, the researchers identified EphA2 as a stress antigen recognized by human Vγ9Vδ1 TCR, with EphA2 being coordinately recognized by ephrin A to activate γδ TCR. The expression of EphA2 was found to be up-regulated in cancer cells undergoing AMPK-dependent metabolic reprogramming, and coexpression of EphA2 and active AMPK in tumors was associated with increased CD3 T cell infiltration in human colorectal cancer tissues.