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


Science immunology, July 2021

Christelle Harly, Stephen Paul Joyce, Charlotte Domblides, Thomas Bachelet, Vincent Pitard, Charlotte Mannat, Angela Pappalardo, Lionel Couzi, Sonia Netzer, Layal Massara, Emilie Obre, Omar Hawchar, Lydia Lartigue, Stéphane Claverol, Carla Cano, Jean-François Moreau, Isabelle Mahouche, Isabelle Soubeyran, Rodrigue Rossignol, Benoit Viollet, Carrie R Willcox, Fiyaz Mohammed, Benjamin E Willcox, Benjamin Faustin, Julie Déchanet-Merville

doi: 10.1126/sciimmunol.aba9010.


Human γδ 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 Vγ9Vδ1 TCR. EphA2 is recognized coordinately by ephrin A to enable γδ 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 γδ TCR to cooperate with a co-receptor to recognize non-MHC-encoded proteins as signals of cellular dysregulation, potentially allowing γδ T cells to sense metabolic energy changes associated with either viral infection or cancer.