Defective Vδ2+ T cell metabolic and functional responses in obesity are reversed with bariatric surgery

Obesity is a chronic progressive disease strongly linked to numerous comorbidities. This is underpinned by a chronic inflammatory environment and significant immune dysregulation. γδ T cells are unconventional T cells that display innate and adaptive characteristics, the predominant one being their independence of MHC restriction. In humans, γδ T cells represent up to 5% of the peripheral blood T cell compartment and are capable of rapidly producing a range of effector cytokines and driving cytotoxic responses. This is critical for protection from both bacterial and viral infections. We investigated circulating γδ T cell metabolic and functional responses in cohorts of people living with obesity (PWO) and people without obesity. We showed that PWO have reduced Vδ2+ T cell frequencies, and their effector responses are diminished following stimulation. We identified that the CD98-LAMTOR5-mTORC1 metabolic axis was critical for functional responses, and demonstrated significant defects in each component of this axis in PWO. Furthermore, STAT5 the initiator of amino acid metabolism was also decreased in PWO. Finally, we showed restoration of this metabolic axis after bariatric surgery, combined with robust improvements in functional responses. Collectively, our data highlighted that obesity drives a reversible dysregulation of Vδ2+ T cells by disrupting cellular metabolism.