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

Area of Science:

• Immunology
• Metabolic pathways in immune cells
• T cell differentiation

Background:

• Metabolic programming influences immune cell function.
• The metabolism of gamma delta (γδ) T cells remains largely unexplored.
• Understanding γδ T cell metabolism is crucial for immune cell lineage control.

Purpose of the Study:

• To investigate the distinct metabolic requirements of γδ T cell subsets.
• To determine the stability and developmental origin of these metabolic signatures.
• To explore the role of γδ T cell metabolism in tumor immunity and obesity.

Main Methods:

• Flow cytometry and metabolic assays to analyze γδ T cell subsets.
• Assessment of mitochondrial mass and activity.
• In vivo studies using mouse models of obesity and tumors.
• Adoptive transfer experiments with manipulated γδ T cells.

Main Results:

• Interferon-γ (IFN-γ)+ γδ T cells primarily use glycolysis.
• Interleukin-17 (IL-17)+ γδ T cells exhibit high oxidative metabolism and mitochondrial activity.
• Distinct metabolic profiles are established early in thymic development and maintained peripherally and within tumors.
• IL-17+ γδ T cells show increased lipid uptake and storage, expanding in obesity and associated tumors.
• Glucose supplementation boosts IFN-γ+ γδ T cell anti-tumor functions.

Conclusions:

• γδ T cell subsets possess intrinsically different metabolic dependencies.
• Metabolic programming of γδ T cells is stable from development through to effector functions in tumors.
• Targeting γδ T cell metabolism, particularly lipid metabolism in IL-17+ cells and glucose availability for IFN-γ+ cells, offers potential for cancer immunotherapy.
• These findings provide insights into effector γδ T cell differentiation and therapeutic manipulation in cancer.