Metformin enhances anti-mycobacterial responses by educating CD8+ T-cell immunometabolic circuits
Julia Böhme, Núria Martínez, Shamin Li, Andrea Lee, Mardiana Marzuki, Anteneh Mehari Tizazu, David F. Ackart, Jessica Haugen Frenkel, Alexandra Todd, Ekta Lachmandas, Josephine Lum, Foo Shihui, Tze Pin Ng, Bernett Lee, Anis Larbi, Mihai G. Netea, Randall J. Basaraba, Reinout van Crevel, Evan W. Newell, Hardy Kornfeld, Amit Singhal
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.