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

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

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. 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.

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