The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

Iosifina P. Foskolou; Pedro P. Cunha; Elena Sánchez-López; Eleanor A. Minogue; Benoît P. Nicolet; Aurélie Guislain; Christian Jorgensen; Sarantos Kostidis; Nordin D. Zandhuis; Laura Barbieri; David Bargiela; Demitris Nathanael; Petros A. Tyrakis; Asis Palazon; Martin Giera; Monika C. Wolkers; Randall S. Johnson

doi:10.1016/j.celrep.2023.113013

The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

Iosifina P. Foskolou^*, Pedro P. Cunha, Elena Sánchez-López, Eleanor A. Minogue, Benoît P. Nicolet, Aurélie Guislain, Christian Jorgensen, Sarantos Kostidis, Nordin D. Zandhuis, Laura Barbieri, David Bargiela, Demitris Nathanael, Petros A. Tyrakis, Asis Palazon, Martin Giera, Monika C. Wolkers, Randall S. Johnson^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8⁺ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8⁺ T cells with exogenous S-2HG, but not R-2HG, increased CD8⁺ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

Original language	English
Article number	113013
Number of pages	23
Journal	Cell Reports
Volume	42
Issue number	9
Early online date	24 Aug 2023
DOIs	https://doi.org/10.1016/j.celrep.2023.113013
Publication status	Published - 26 Sept 2023

Keywords

2-hydroxyglutarate
adoptive cell transfer
CD8+ T cell function
CD8+ T cell memory
CP: Immunology
oncometabolites

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10.1016/j.celrep.2023.113013

The two enantiomers of 2-hydroxyglutarateFinal published version, 3.87 MBLicence: CC BY

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Foskolou, I. P., Cunha, P. P., Sánchez-López, E., Minogue, E. A., Nicolet, B. P., Guislain, A., Jorgensen, C., Kostidis, S., Zandhuis, N. D., Barbieri, L., Bargiela, D., Nathanael, D., Tyrakis, P. A., Palazon, A., Giera, M., Wolkers, M. C., & Johnson, R. S. (2023). The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function. Cell Reports, 42(9), Article 113013. https://doi.org/10.1016/j.celrep.2023.113013

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title = "The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function",

abstract = "2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8+ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.",

keywords = "2-hydroxyglutarate, adoptive cell transfer, CD8+ T cell function, CD8+ T cell memory, CP: Immunology, oncometabolites",

author = "Foskolou, {Iosifina P.} and Cunha, {Pedro P.} and Elena S{\'a}nchez-L{\'o}pez and Minogue, {Eleanor A.} and Nicolet, {Beno{\^i}t P.} and Aur{\'e}lie Guislain and Christian Jorgensen and Sarantos Kostidis and Zandhuis, {Nordin D.} and Laura Barbieri and David Bargiela and Demitris Nathanael and Tyrakis, {Petros A.} and Asis Palazon and Martin Giera and Wolkers, {Monika C.} and Johnson, {Randall S.}",

note = "Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = sep,

day = "26",

doi = "10.1016/j.celrep.2023.113013",

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Foskolou, IP, Cunha, PP, Sánchez-López, E, Minogue, EA, Nicolet, BP, Guislain, A, Jorgensen, C, Kostidis, S, Zandhuis, ND, Barbieri, L, Bargiela, D, Nathanael, D, Tyrakis, PA, Palazon, A, Giera, M, Wolkers, MC & Johnson, RS 2023, 'The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function', Cell Reports, vol. 42, no. 9, 113013. https://doi.org/10.1016/j.celrep.2023.113013

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AU - Foskolou, Iosifina P.

AU - Cunha, Pedro P.

AU - Sánchez-López, Elena

AU - Minogue, Eleanor A.

AU - Nicolet, Benoît P.

AU - Guislain, Aurélie

AU - Jorgensen, Christian

AU - Kostidis, Sarantos

AU - Zandhuis, Nordin D.

AU - Barbieri, Laura

AU - Bargiela, David

AU - Nathanael, Demitris

AU - Tyrakis, Petros A.

AU - Palazon, Asis

AU - Giera, Martin

AU - Wolkers, Monika C.

AU - Johnson, Randall S.

PY - 2023/9/26

Y1 - 2023/9/26

N2 - 2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8+ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

AB - 2-Hydroxyglutarate (2HG) is a byproduct of the tricarboxylic acid (TCA) cycle and is readily detected in the tissues of healthy individuals. 2HG is found in two enantiomeric forms: S-2HG and R-2HG. Here, we investigate the differential roles of these two enantiomers in cluster of differentiation (CD)8+ T cell biology, where we find they have highly divergent effects on proliferation, differentiation, and T cell function. We show here an analysis of structural determinants that likely underlie these differential effects on specific α-ketoglutarate (αKG)-dependent enzymes. Treatment of CD8+ T cells with exogenous S-2HG, but not R-2HG, increased CD8+ T cell fitness in vivo and enhanced anti-tumor activity. These data show that S-2HG and R-2HG should be considered as two distinct and important actors in the regulation of T cell function.

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KW - adoptive cell transfer

KW - CD8+ T cell function

KW - CD8+ T cell memory

KW - CP: Immunology

KW - oncometabolites

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SN - 2211-1247

VL - 42

JO - Cell Reports

JF - Cell Reports

IS - 9

M1 - 113013

ER -

The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

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Keywords

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