Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis

Madhav Kishore, Kenneth C.P. Cheung, Hongmei Fu, Fabrizia Bonacina, Guosu Wang, David Coe, Eleanor J. Ward, Alessandra Colamatteo, Maryam Jangani, Andrea Baragetti, Giuseppe Matarese, David M. Smith, Robert Haas, Claudio Mauro, David C. Wraith, Klaus Okkenhaug, Alberico L. Catapano, Veronica De Rosa, Giuseppe D. Norata, Federica M. Marelli-Berg

Research output: Contribution to journalArticle

Abstract

Migration of activated regulatory T (Treg) cells to inflamed tissue is crucial for their immune-modulatory function. While metabolic reprogramming during Treg cell differentiation has been extensively studied, the bioenergetics of Treg cell trafficking remains undefined. We have investigated the metabolic demands of migrating Treg cells in vitro and in vivo. We show that glycolysis was instrumental for their migration and was initiated by pro-migratory stimuli via a PI3K-mTORC2-mediated pathway culminating in induction of the enzyme glucokinase (GCK). Subsequently, GCK promoted cytoskeletal rearrangements by associating with actin. Treg cells lacking this pathway were functionally suppressive but failed to migrate to skin allografts and inhibit rejection. Similarly, human carriers of a loss-of-function GCK regulatory protein gene—leading to increased GCK activity—had reduced numbers of circulating Treg cells. These cells displayed enhanced migratory activity but similar suppressive function, while conventional T cells were unaffected. Thus, GCK-dependent glycolysis regulates Treg cell migration. Regulatory T cell localization to inflammatory sites is key to their homeostatic function. Kishore and colleagues demonstrate that Treg cell migration requires the activation of glycolysis by the enzyme glucokinase induced via a Treg cell-selective PI3K-mTORC2 pathway.

Original languageEnglish
Pages (from-to)875-889.e10
JournalImmunity
Volume47
Issue number5
DOIs
Publication statusPublished - Nov 21 2017

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Keywords

  • CD28
  • CTLA-4
  • glycolysis
  • metabolism
  • migration
  • mTOR
  • regulatory T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

Kishore, M., Cheung, K. C. P., Fu, H., Bonacina, F., Wang, G., Coe, D., Ward, E. J., Colamatteo, A., Jangani, M., Baragetti, A., Matarese, G., Smith, D. M., Haas, R., Mauro, C., Wraith, D. C., Okkenhaug, K., Catapano, A. L., De Rosa, V., Norata, G. D., & Marelli-Berg, F. M. (2017). Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis. Immunity, 47(5), 875-889.e10. https://doi.org/10.1016/j.immuni.2017.10.017