Unique metabolic and functional phenotypes of IFNγ-producing γδT cells in the adipose tissue

Abstract

γδT cells represent a type of innate T cells that are thymically pre-programmed, poised to rapidly respond, and can be activated by various signals. They are promising candidates for allogeneic cell therapies, owing to their independence from major histocompatibility complex (MHC) recognition and potent antitumor activities. In mice, they can be categorized into IL-17 producing γδT (γδ17) cells and IFNγ-producing γδT (γδIFN) cells. As the two subsets exhibit distinct metabolic features at steady state, boosting their metabolism can result in divergent effects on tumor growth. Despite the potential of γδIFN cells in tumor killing and cell therapy, the tissue-specific metabolic and functional adaptations of γδIFN cells are poorly understood. Leveraging single-cell RNA sequencing (scRNA-seq) data, we revealed that Ly6C+ γδIFN cells were enriched in the adipose tissue, and these cells in the adipose tissue exhibited heightened expression of cytotoxic markers and average expression of genes in cholesterol biosynthesis, compared to Ly6C+ γδIFN cells in other tissues. We further demonstrated that the metabolic and functional signatures of adipose-resident Ly6C+ γδIFN cells were likely influenced by the adipose tissue microenvironment, as exposure to fat-conditioned media (FCM) augmented NKG2D expression and neutral lipid content of in vitro expanded Ly6C+ γδIFN cells. Moreover, our findings underscored a direct correlation between cholesterol biosynthesis and cytotoxic markers, as cholesterol treatment led to downregulation of both phenotypes in in vitro expanded γδIFN cells. Future investigations will delve deeper into the mechanistic link between cholesterol biosynthesis and cytotoxicity markers in γδIFN cells, with the aim of enhancing their cytotoxic potential through targeted metabolic interventions.