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 Wraith; Klaus Okkenhaug; Alberico L Catapano; Veronica De Rosa; Giuseppe D Norata; Federica M Marelli-Berg

doi:10.1016/j.immuni.2017.10.017

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 Wraith, Klaus Okkenhaug, Alberico L Catapano, Veronica De Rosa, Giuseppe D Norata, Federica M Marelli-Berg

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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.

Original language	English
Pages (from-to)	875-889.e10
Journal	Immunity
Volume	47
Issue number	5
DOIs	https://doi.org/10.1016/j.immuni.2017.10.017
Publication status	Published - 21 Nov 2017

Keywords

regulatory T cells
metabolism
migration
glycolysis
mTOR
CD28
CTLA-4

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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., 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

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title = "Regulatory T cell migration is dependent on glucokinase-mediated glycolysis",

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 = "regulatory T cells, metabolism, migration, glycolysis, mTOR, CD28, CTLA-4",

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

year = "2017",

month = nov,

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doi = "10.1016/j.immuni.2017.10.017",

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Kishore, M, Cheung, KCP, Fu, H, Bonacina, F, Wang, G, Coe, D, Ward, EJ, Colamatteo, A, Jangani, M, Baragetti, A, Matarese, G, Smith, DM, Haas, R, Mauro, C , Wraith, D, Okkenhaug, K, Catapano, AL, De Rosa, V, Norata, GD & Marelli-Berg, FM 2017, 'Regulatory T cell migration is dependent on glucokinase-mediated glycolysis', Immunity, vol. 47, no. 5, pp. 875-889.e10. https://doi.org/10.1016/j.immuni.2017.10.017

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T1 - Regulatory T cell migration is dependent on glucokinase-mediated glycolysis

AU - Kishore, Madhav

AU - Cheung, Kenneth C P

AU - Fu, Hongmei

AU - Bonacina, Fabrizia

AU - Wang, Guosu

AU - Coe, David

AU - Ward, Eleanor J

AU - Colamatteo, Alessandra

AU - Jangani, Maryam

AU - Baragetti, Andrea

AU - Matarese, Giuseppe

AU - Smith, David M

AU - Haas, Robert

AU - Mauro, Claudio

AU - Wraith, David

AU - Okkenhaug, Klaus

AU - Catapano, Alberico L

AU - De Rosa, Veronica

AU - Norata, Giuseppe D

AU - Marelli-Berg, Federica M

PY - 2017/11/21

Y1 - 2017/11/21

N2 - 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.

AB - 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.

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KW - metabolism

KW - migration

KW - glycolysis

KW - mTOR

KW - CD28

KW - CTLA-4

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DO - 10.1016/j.immuni.2017.10.017

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SN - 1074-7613

VL - 47

SP - 875-889.e10

JO - Immunity

JF - Immunity

IS - 5

ER -

Regulatory T cell migration is dependent on glucokinase-mediated glycolysis

Abstract

Keywords

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