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

By Julia Bohme, Nuria Martinez, Shamin Li, Andrea Lee, Mardiana Marzuki, Anteneh Tizazu, David Ackart, Jessica Frenkel, Alexandra Todd, Ekta Lachmandas, Josephine Lum, Foo Shihui, Tze Pin Ng, Bernett Lee, Anis Larbi, Mihai Netea, Randall Basaraba, Reinout van Crevel, Evan W Newell, Hardy Kornfeld, Amit Singhal

Posted 27 Aug 2020
bioRxiv DOI: 10.1101/2020.08.26.269217 (published DOI: 10.1038/s41467-020-19095-z)

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 (1) mitochondrial mass, oxidative phosphorylation, and fatty acid oxidation; (2) survival capacity; and (3) 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. ### Competing Interest Statement The authors have declared no competing interest.

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