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

Cell Reports (Sep 2023)

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

Affiliations

Iosifina P. Foskolou: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK; Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden; Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory Amsterdam University Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands; Corresponding author
Pedro P. Cunha: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK; Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden
Elena Sánchez-López: Leiden University Medical Center, Center for Proteomics and Metabolomics, Albinusdreef 2, 2333ZA Leiden, the Netherlands
Eleanor A. Minogue: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK
Benoît P. Nicolet: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory Amsterdam University Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Aurélie Guislain: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory Amsterdam University Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Christian Jorgensen: Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark
Sarantos Kostidis: Leiden University Medical Center, Center for Proteomics and Metabolomics, Albinusdreef 2, 2333ZA Leiden, the Netherlands
Nordin D. Zandhuis: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory Amsterdam University Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Laura Barbieri: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK
David Bargiela: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK
Demitris Nathanael: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK
Petros A. Tyrakis: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK
Asis Palazon: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK
Martin Giera: Leiden University Medical Center, Center for Proteomics and Metabolomics, Albinusdreef 2, 2333ZA Leiden, the Netherlands
Monika C. Wolkers: Department of Hematopoiesis, Sanquin Research and Landsteiner Laboratory Amsterdam University Medical Center, University of Amsterdam, 1066 CX Amsterdam, the Netherlands; Oncode Institute, 3521 AL Utrecht, the Netherlands
Randall S. Johnson: Department of Physiology, Development and Neuroscience, University of Cambridge, Downing Site, Cambridge CB2 3EG, UK; Department of Cell and Molecular Biology (CMB), Karolinska Institutet, Solnavägen 9, 171 65 Solna, Sweden; Corresponding author

Journal volume & issue: Vol. 42, no. 9
p. 113013

Abstract

Read online

Summary: 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.

CP: Immunology

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

About the journal

Abstract

Keywords