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

Julia Böhme, Nuria Martinez, Shamin Li, Andrea Lee, Mardiana Marzuki, Anteneh Mehari Tizazu, David Ackart, Jessica Haugen Frenkel, Alexandra Todd, Ekta Lachmandas, Josephine Lum, Foo Shihui, Tze Pin Ng, Bernett Lee, Anis Larbi, Mihai G. Netea, Randall Basaraba, Reinout Crevel, Evan Newell, Hardy Kornfeld and Amit Singhal ()
Additional contact information
Julia Böhme: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Nuria Martinez: University of Massachusetts Medical School
Shamin Li: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Andrea Lee: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Mardiana Marzuki: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Anteneh Mehari Tizazu: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
David Ackart: Immunology & Pathology, Colorado State University
Jessica Haugen Frenkel: Immunology & Pathology, Colorado State University
Alexandra Todd: Immunology & Pathology, Colorado State University
Ekta Lachmandas: Radboud University Medical Center
Josephine Lum: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Foo Shihui: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Tze Pin Ng: National University Health System, National University of Singapore
Bernett Lee: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Anis Larbi: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Mihai G. Netea: Radboud University Medical Center
Randall Basaraba: Immunology & Pathology, Colorado State University
Reinout Crevel: Radboud University Medical Center
Evan Newell: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)
Hardy Kornfeld: University of Massachusetts Medical School
Amit Singhal: Singapore Immunology Network (SIgN), Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2020, vol. 11, issue 1, 1-15

Abstract: Abstract Patients with type 2 diabetes (T2D) have a lower risk of Mycobacterium tuberculosis infection, progression from infection to tuberculosis (TB) disease, TB morality and TB recurrence, when being treated with metformin. However, a detailed mechanistic understanding of these protective effects is lacking. Here, we use mass cytometry to show that metformin treatment expands a population of memory-like antigen-inexperienced CD8+CXCR3+ T cells in naive mice, and in healthy individuals and patients with T2D. 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 do not exhibit this metformin-mediated metabolic programming. In BCG-vaccinated mice and guinea pigs, metformin enhances immunogenicity and protective efficacy against M. tuberculosis challenge. Collectively, these results demonstrate an important function of CD8+ T cells in metformin-derived host metabolic-fitness towards M. tuberculosis infection.

Date: 2020
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DOI: 10.1038/s41467-020-19095-z

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