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Nat Commun . 2020 Oct 16

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

Miguel J Lobo, Laia Reverte-Salisa, Ying-Chi Chao, Andreas Koschinski, Frank Gesellchen, Gunasekaran Subramaniam, He Jiang, Samuel Pace, Natasha Larcom, Ester Paolocci, Alexander Pfeifer, Sara Zanivan, Manuela Zaccolo, Helin Tercan, Niels P Riksen, Leo A B Joosten, Mihai G Netea, Siroon Bekkering, Maria Elisa Mancuso, Johnny Mahlangu, Robert Sidonio Jr, Peter Trask, Marianne Uguen, Tiffany Chang, Midori Shima, Guy Young, Johannes Oldenburg, Sylvia von Mackensen, Andreas Tiede, Santiago Bonanad, Amparo Santamaria, Georg Goldmann, Mariana Canaro, Antonio Palomero, Luis J G Frade, Juan Eduardo Megias-Vericat, Fernanda Martinez, Faustino Garcia Candel, Victor Jimenez Yuste, Monika Sparber-Sauer, Susan Halimeh, Daniela Adolf, Martin Hukauf, Jan Reichmann, Johannes Oldenburg, Artur Słomka, Tudor Mocan, Bingduo Wang, Iuliana Nenu, Sabine K Urban, Maria Gonzales-Carmona, Ingo G H Schmidt-Wolf, Veronika Lukacs-Kornek, Christian P Strassburg, Zeno Spârchez, Miroslaw Kornek, Hans-Peter Erasmus, Rukiye Bektas, Katharina Orland, Svetlozara Trifonova, Wen-Yi Gu, Frank Erhard Uschner, Maximilian J Brol, Johannes Chang, Michael Praktiknjo, Christian P Strassburg, Jonel Trebicka, Christian Jansen, Erik B van den Akker, Stella Trompet, Jurriaan J H Barkey Wolf, Marian Beekman, H Eka D Suchiman, Joris Deelen, Folkert W Asselbergs, Eric Boersma, Davy Cats, Petra M Elders, J Marianne Geleijnse, M Arfan Ikram, Margreet Kloppenburg, Haillang Mei, Ingrid Meulenbelt, Simon P Mooijaart, Rob G H H Nelissen, Mihai G Netea, Brenda W J H Penninx, Mariska Slofstra, Coen D A Stehouwer, Morris A Swertz, Charlotte E Teunissen, Gisela M Terwindt, Leen M 't Hart, Arn M J M van den Maagdenberg, Pim van der Harst, Iwan C C van der Horst, Carla J H van der Kallen, Marleen M J van Greevenbroek, W Erwin van Spil, Cisca Wijmenga, Alexandra Zhernakova, Aeilko H Zwinderman, Naveed Sattar, J Wouter Jukema, Cornelia M van Duijn, Dorret I Boomsma, Marcel J T Reinders, P Eline Slagboom, Narine Mesropyan, Patrick Kupczyk, Leona Dold, Tobias J Weismüller, Alois M Sprinkart, Burkhart Mädler, Claus C Pieper, Daniel Kuetting, Christian P Strassburg, Ulrike Attenberger, Julian A Luetkens, Laura K Esser, Vittorio Branchi, Sonia Leonardelli, Natalie Pelusi, Adrian G Simon, Niklas Klümper, Jörg Ellinger, Stefan Hauser, Maria A Gonzalez-Carmona, Manuel Ritter, Glen Kristiansen, Hubert Schorle, Michael Hölzel, Marieta I Toma, Cheryl Y Brown, Timothy Sadlon, Christopher M Hope, Ying Y Wong, Soon Wong, Ning Liu, Holly Withers, Katherine Brown, Veronika Bandara, Batjargal Gundsambuu, Stephen Pederson, James Breen, Sarah Anne Robertson, Alistair Forrest, Marc Beyer, Simon Charles Barry, 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 van Crevel, Evan Newell, Hardy Kornfeld, Amit Singhal

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.

PMID: 33067434