Sensing metabolic shifts
Human γδ T cells play a critical role in surveillance against infection and cancer and use various mechanisms to sense metabolic changes associated with these assaults. Harly et al. describe a role for the stress ligand ephrin type-A receptor 2 (EphA2), which is up-regulated on cancer cells and is recognized by the human Vγ9Vδ1 T cell receptor (TCR) together with ephrin A. EphA2 up-regulation was mediated by metabolic changes in cancer cells caused by AMP-activated protein kinase (AMPK) activity. Increased coexpression of EphA2 and AMPK in tumor tissues was also linked to greater T cell infiltration in human colorectal cancer tissue. These findings suggest that human γδ T cells can sense changes in stress ligands and trigger responses caused by metabolic changes associated with infection or cancer.
Abstract
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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