Regulatory T Cell Migration Is Dependent on Glucokinase-Mediated Glycolysis

被引：214

作者：

Kishore, Madhav ^{[1
]}

Cheung, Kenneth C. P. ^{[1
]}

Fu, Hongmei ^{[1
]}

Bonacina, Fabrizia ^{[2
]}

Wang, Guosu ^{[1
]}

Coe, David ^{[1
]}

Ward, Eleanor J. ^{[1
]}

Colamatteo, Alessandra ^{[3
]}

Jangani, Maryam ^{[1
]}

Baragetti, Andrea ^{[2
]}

Matarese, Giuseppe ^{[3
,4
]}

Smith, David M. ^{[5
]}

Haas, Robert ^{[1
]}

Mauro, Claudio ^{[1
]}

Wraith, David C. ^{[6
]}

Okkenhaug, Klaus ^{[7
]}

Catapano, Alberico L. ^{[2
,8
]}

De Rosa, Veronica ^{[3
]}

Norata, Giuseppe D. ^{[2
,9
]}

Marelli-Berg, Federica M. ^{[1
]}

机构：

[1] Queen Mary Univ London, William Harvey Res Inst, London EC1M 6BQ, England

[2] Univ Milan, Dept Pharmacol & Biomol Sci, I-20133 Milan, Italy

[3] CNR, IEOS, I-80131 Naples, Italy

[4] Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, I-80131 Naples, Italy

[5] AstraZeneca, Discovery Sci Innovat Med & Early Dev Biotech Uni, Cambridge CB4 0WG, Cambs, England

[6] Univ Birmingham, Inst Immunol & Immunotherapy, Birmingham B15 2TT, W Midlands, England

[7] Babraham Inst, Lab Lymphocyte Signalling & Dev, Cambridge CB22 3AT, England

[8] IRCCS Multimed Hosp, I-20138 Milan, Italy

[9] Curtin Univ, Sch Biomed Sci, Curtin Hlth Innovat Res Inst, Perth, WA 6102, Australia

来源：

IMMUNITY | 2017年 / 47卷 / 05期

基金：

英国生物技术与生命科学研究理事会;

关键词：

GENERAL-POPULATION; SIGNALING PATHWAY; MAMMALIAN TARGET; CD28; CTLA-4; ACTIVATION; RECEPTOR; DIFFERENTIATION; METABOLISM; EXPRESSION;

D O I：

10.1016/j.immuni.2017.10.017

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

071005 [微生物学]; 100108 [医学免疫学];

摘要：

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.

引用

页码：875 / +

页数：25

共 51 条

[1]

Telomere shortening over 6 years is associated with increased subclinical carotid vascular damage and worse cardiovascular prognosis in the general population [J].