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

Bohme, J.; Martinez, N.; Li, S.; Lee, A.; Marzuki, M.; Tizazu, A.; Ackart, D.; Frenkel, J.; Todd, A.; Lachmandas, E.; Lum, J.; Shihui, F.; Ng, T. P.; Lee, B.; Larbi, A.; Netea, M.; Basaraba, R.; van Crevel, R.; Newell, E.; Kornfeld, H.; Singhal, A.

doi:10.1101/2020.08.26.269217

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bioRxiv · 10.1101/2020.08.26.269217

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

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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 metformins 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 naive 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.

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Bohme, J., Martinez, N., Li, S., Lee, A., Marzuki, M., Tizazu, A., Ackart, D., Frenkel, J., Todd, A., Lachmandas, E., Lum, J., Shihui, F., Ng, T. P., Lee, B., Larbi, A., Netea, M., Basaraba, R., van Crevel, R., Newell, E., Kornfeld, H., Singhal, A.. 2020-08-27. Metformin enhances anti-mycobacterial responses by educating immunometabolic circuits of CD8+ T cells. https://doi.org/10.1101/2020.08.26.269217

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