Human γδ T cell sensing of AMPK-dependent metabolic tumor reprogramming through TCR recognition of EphA2
Christelle Harly
(1)
,
Stephen Paul
(2)
,
Charlotte Domblides
(1)
,
Thomas Bachelet
(1)
,
Vincent Pitard
(1, 3)
,
Charlotte Mannat
(1)
,
Angela Pappalardo
(1)
,
Lionel Couzi
(1, 4)
,
Sonia Netzer
(1)
,
Layal Massara
(1)
,
Emilie Obre
(5, 6, 7)
,
Omar Hawchar
(1)
,
Lydia Lartigue
(8, 9)
,
Stéphane Claverol
(5)
,
Carla Cano
(10)
,
Jean-François Moreau
(1, 11)
,
Isabelle Mahouche
(8)
,
Isabelle Soubeyran
(8)
,
Rodrigue Rossignol
(5, 6, 7, 12)
,
Benoit Viollet
(13, 14)
,
Carrie R Willcox
(2)
,
Fiyaz Mohammed
(2)
,
Benjamin E Willcox
(2)
,
Benjamin Faustin
(1, 15)
,
Julie Déchanet-Merville
(1, 3)
1
ImmunoConcept -
Immunology from Concept and Experiments to Translation
2 University of Birmingham [Birmingham]
3 UMS3427 - INSERM US005 - TBM-Core [Bordeaux]
4 CHU Bordeaux
5 CGFB - Centre Génomique Fonctionnelle Bordeaux [Bordeaux]
6 Cellomet [CHU Pellegrin, Bordeaux]
7 UB - Université de Bordeaux
8 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
9 Institut Bergonié [Bordeaux]
10 ImCheck Therapeutics [Marseille]
11 Laboratoire d'immunologie et d'immunogénétique [CHU Bordeaux]
12 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
13 IC UM3 (UMR 8104 / U1016) - Institut Cochin
14 UPD5 - Université Paris Descartes - Paris 5
15 Janssen Research & Development
2 University of Birmingham [Birmingham]
3 UMS3427 - INSERM US005 - TBM-Core [Bordeaux]
4 CHU Bordeaux
5 CGFB - Centre Génomique Fonctionnelle Bordeaux [Bordeaux]
6 Cellomet [CHU Pellegrin, Bordeaux]
7 UB - Université de Bordeaux
8 ACTION - Actions for OnCogenesis understanding and Target Identification in ONcology
9 Institut Bergonié [Bordeaux]
10 ImCheck Therapeutics [Marseille]
11 Laboratoire d'immunologie et d'immunogénétique [CHU Bordeaux]
12 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
13 IC UM3 (UMR 8104 / U1016) - Institut Cochin
14 UPD5 - Université Paris Descartes - Paris 5
15 Janssen Research & Development
Christelle Harly
- Fonction : Auteur
- PersonId : 1067880
- IdHAL : harly-christelle
- ORCID : 0000-0002-8045-9166
- IdRef : 159246555
Charlotte Domblides
- Fonction : Auteur
- PersonId : 776197
- ORCID : 0000-0002-9455-0657
Vincent Pitard
- Fonction : Auteur
- PersonId : 756114
- ORCID : 0000-0001-6380-2308
Lionel Couzi
- Fonction : Auteur
- PersonId : 756218
- ORCID : 0000-0002-9213-6196
- IdRef : 076993671
Stéphane Claverol
- Fonction : Auteur
- PersonId : 760094
- ORCID : 0000-0001-5315-2823
- IdRef : 074185934
Isabelle Soubeyran
- Fonction : Auteur
- PersonId : 762161
- ORCID : 0000-0001-7501-7622
Benoit Viollet
- Fonction : Auteur
- PersonId : 15580
- IdHAL : benoit-viollet
- ORCID : 0000-0002-0121-0224
- IdRef : 187119279
Résumé
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.
Domaines
Cancer
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