Metformin and 2-Deoxyglucose Collaboratively Suppress Human CD4⁺ T Cell Effector Functions and Activation-Induced...

Area of Science:

• Immunology
• Metabolic pathways
• T cell biology

Background:

• Metabolic reprogramming is crucial for T cell activation and differentiation.
• Targeting metabolic pathways in T cells offers a therapeutic strategy for autoimmune diseases.
• Metformin and 2-deoxyglucose (2-DG) inhibit key metabolic pathways like oxidative phosphorylation and glycolysis.

Purpose of the Study:

• To investigate the combined effects of metformin and 2-DG on primary human CD4+ T cells.
• To elucidate the impact of this combination therapy on T cell activation and metabolic reprogramming.
• To identify the underlying molecular mechanisms, including transcriptional regulation.

Main Methods:

• Treatment of activated primary human CD4+ T cells with metformin and 2-DG.
• Assessment of T cell proliferation and Interferon-gamma (IFN-γ) production.
• Analysis of metabolic transcriptional programs, including MYC and HIF-1A.
• Investigation of mTORC1 signaling pathway involvement.

Main Results:

• Metformin + 2-DG combination treatment significantly suppressed IFN-γ production and cell proliferation more effectively than individual treatments.
• The combination therapy induced significant remodeling of activation-induced metabolic transcriptional programs in human T cells.
• Suppression of key transcriptional regulators MYC and HIF-1A was observed.
• Metformin + 2-DG suppressed MYC-dependent metabolic genes independently of mTORC1 signaling.

Conclusions:

• Metformin and 2-DG combination therapy is a potent suppressor of activated human T cell functions.
• This combination therapy significantly alters T cell metabolic reprogramming by targeting MYC and HIF-1A.
• Findings provide a rationale for developing novel combination therapies targeting metabolic networks in T cells for autoimmune diseases.