Distinct Metabolic Programs Established In The Thymus Control Effector Functions Of Gamma Delta T Cell Subsets In Tumor Microenvironments

Metabolic programming controls immune cell lineages and functions, but little is known about gamma delta T cell metabolism. Here, we found that gamma delta T cell subsets making either interferon-gamma (IFN-gamma) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-gamma(+) gamma delta T cells were almost exclusively dependent on glycolysis, IL-17(+) gamma delta T cells strongly engaged oxidative metabolism, with increased mitochondrial mass and activity. These distinct metabolic signatures were surprisingly imprinted early during thymic development and were stably maintained in the periphery and within tumors. Moreover, pro-tumoral IL-17(+) gamma delta T cells selectively showed high lipid uptake and intracellular lipid storage and were expanded in obesity and in tumors of obese mice. Conversely, glucose supplementation enhanced the antitumor functions of IFN-gamma(+) gamma delta T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector gamma delta T cells and their manipulation in cancer immunotherapy.