Distinct metabolic programs established in the thymus control effector functions of γδ T cell subsets in tumor microenvironments

© The Author(s), under exclusive licence to Springer Nature America, Inc. 2021
Metabolic programming controls immune cell lineages and functions, but little is known about γδ T cell metabolism. Here, we found that γδ T cell subsets making either interferon-γ (IFN-γ) or interleukin (IL)-17 have intrinsically distinct metabolic requirements. Whereas IFN-γ+ γδ T cells were almost exclusively dependent on glycolysis, IL-17+ γδ 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+ γδ 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-γ+ γδ T cells and reduced tumor growth upon adoptive transfer. These findings have important implications for the differentiation of effector γδ T cells and their manipulation in cancer immunotherapy.
This work was supported by the Wellcome Trust (092973/Z/10/Z to D.J.P.), Biotechnology and Biological Sciences Research Council (BBSRC) UK (BB/R017808/1 to D.J.P.), European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 646701 to B.S.-S.; StG_679173 to L.L.), Science Foundation Ireland (SFI) (16/FRL/3865 to L.L.), NIH (NS115064, HG008155, AG062377 to M.K.), NIH (R01 AI134861 and metabolic core grant S10 OD020100 to L.L.), Fundação Astrazeneca (Prémio FAZ Ciência 2019 to B.S.-S. and N.L.) and PAC-PRECISE LISBOA-01-0145-FEDER-016394, co-funded by FEDER (POR Lisboa 2020 (Programa Operacional Regional de Lisboa, do Portugal 2020)) and Fundação para a Ciência e a Tecnologia (Portugal). N.L. is supported by a postdoctoral fellowship from EMBO (ALTF 752-2018); S.M. was supported by a studentship from the Medical Research Council (MRC) UK; G.F. is supported by the European Union’s Horizon 2020 research and innovation programme under the Marie Skłodowska-Curie grant agreement no. 752932; and A.D., S.C., L.D. and H.P. are supported by Irish Research Council fellowships.