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Immunity. 2017 Nov 21;47(5):875-889.e10. doi: 10.1016/j.immuni.2017.10.017.

Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis.

Author information

1
William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK.
2
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy.
3
Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples 80131, Italy.
4
Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Naples 80131, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," Naples 80131, Italy.
5
Discovery Sciences, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Cambridge, Cambridgeshire CB40WG, UK.
6
Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK.
7
Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge CB22 3AT, UK.
8
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy; IRCCS Multimedica Hospital, Milan 20138, Italy.
9
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan 20133, Italy; School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6102, Australia.
10
William Harvey Research Institute, Queen Mary University of London, London EC1M6BQ, UK. Electronic address: f.marelli-berg@qmul.ac.uk.

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.

KEYWORDS:

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

PMID:
29166588
PMCID:
PMC5714502
DOI:
10.1016/j.immuni.2017.10.017
[Indexed for MEDLINE]
Free PMC Article

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