Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8 ⁺ T cells

Abstract Diabetic patients taking metformin have lower risk for Mycobacterium tuberculosis ( Mtb ) infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence. However, a detailed mechanistic understanding of metformin’s protective immunological benefits on host resistance to TB is lacking. In this study, using mass cytometry we show that metformin treatment expands memory-like antigen-inexperienced CD8 + CXCR3 + T cells in naïve mice, and in healthy and diabetic humans. Metformin-educated CD8 + T cells have increased (i) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (ii) survival capacity; and (iii) anti-mycobacterial properties. CD8 + T cells from CXCR3 −/− mice did not exhibit metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhanced immunogenicity and protective efficacy against Mtb challenge. Collectively, our results demonstrate an important role of CD8 + T cells in metformin-derived host metabolic-fitness towards Mtb infection.