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
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.
