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:https://doi.org/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

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

4 Citations (Scopus)

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
Journal	Cell reports
Volume	42
Issue number	9
DOIs	https://doi.org/10.1016/j.celrep.2023.113013
Publication status	Published - 26 Sept 2023

Keywords

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

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https://doi.org/10.1016/j.celrep.2023.113013

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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, CD8+ T cell function, CD8+ T cell memory, CP: Immunology, adoptive cell transfer, 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 = "Funding Information: We thank Darren Cawkill, Mark Hoogenboezem, Ken G.C. Smith, and Pedro Velica for helpful comments and advice and Cristina M. Branco for recruitment and support of P.P.C.; the Cambridge NIHR BRC Cell Phenotyping Hub and the flow cytometry facility from the School of the Biological Sciences; and the animal caretakers of the NKI and the Sanquin FACS facility. This work was supported by Apollo Therapeutics, the Knut and Alice Wallenberg Scholar Award, the Swedish Medical Research Council (Vetenskapsrdet 2019-01485), the Swedish Cancer Fund (Cancerfonden, CAN2018/808), the Swedish Children's Cancer Fund (Barncancerfonden PR2020-007), and the Wellcome Trust Principal Fellowship Award (214283/Z/18/Z) to R.S.J.; the Evelyn Trust Cambridge (Patrick Sisson's Research Fellowship) and the Karolinska Institutet (Jonas S{\"o}derquists Fellowship) awarded to I.P.F.; and the Foundation for Science and Technology of Portugal (FCT) scholarship (SFRH/BD/115612/2016) awarded to P.P.C. Conceptualization, I.P.F. and R.S.J.; methodology, I.P.F. P.P.C. E.S.-L. C.J. and R.S.J.; software, B.P.N. D.B. and C.J.; investigation, I.P.F. P.P.C. E.S.-L. E.A.M. A.G. C.J. S.K. N.D.Z. L.B. and D.N.; writing – original draft, I.P.F. and R.S.J.; writing – review & editing, all authors; funding acquisition, I.P.F. and R.S.J.; supervision, M.G. M.C.W. and R.S.J.; project administration, I.P.F. and R.S.J. The authors declare no competing interests. One or more of the authors of this paper self-identifies as a gender minority in their field of research. Funding Information: We thank Darren Cawkill, Mark Hoogenboezem, Ken G.C. Smith, and Pedro Velica for helpful comments and advice and Cristina M. Branco for recruitment and support of P.P.C.; the Cambridge NIHR BRC Cell Phenotyping Hub and the flow cytometry facility from the School of the Biological Sciences; and the animal caretakers of the NKI and the Sanquin FACS facility. This work was supported by Apollo Therapeutics, the Knut and Alice Wallenberg Scholar Award, the Swedish Medical Research Council (Vetenskapsrdet 2019-01485), the Swedish Cancer Fund (Cancerfonden, CAN2018/808), the Swedish Children{\textquoteright}s Cancer Fund (Barncancerfonden PR2020-007), and the Wellcome Trust Principal Fellowship Award (214283/Z/18/Z) to R.S.J.; the Evelyn Trust Cambridge (Patrick Sisson{\textquoteright}s Research Fellowship) and the Karolinska Institutet (Jonas S{\"o}derquists Fellowship) awarded to I.P.F.; and the Foundation for Science and Technology of Portugal (FCT) scholarship ( SFRH/BD/115612/2016 ) awarded to P.P.C. Publisher Copyright: {\textcopyright} 2023",

year = "2023",

month = sep,

day = "26",

doi = "https://doi.org/10.1016/j.celrep.2023.113013",

language = "English",

volume = "42",

journal = "Cell reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "9",

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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

TY - JOUR

T1 - The two enantiomers of 2-hydroxyglutarate differentially regulate cytotoxic T cell function

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.

N1 - Funding Information: We thank Darren Cawkill, Mark Hoogenboezem, Ken G.C. Smith, and Pedro Velica for helpful comments and advice and Cristina M. Branco for recruitment and support of P.P.C.; the Cambridge NIHR BRC Cell Phenotyping Hub and the flow cytometry facility from the School of the Biological Sciences; and the animal caretakers of the NKI and the Sanquin FACS facility. This work was supported by Apollo Therapeutics, the Knut and Alice Wallenberg Scholar Award, the Swedish Medical Research Council (Vetenskapsrdet 2019-01485), the Swedish Cancer Fund (Cancerfonden, CAN2018/808), the Swedish Children's Cancer Fund (Barncancerfonden PR2020-007), and the Wellcome Trust Principal Fellowship Award (214283/Z/18/Z) to R.S.J.; the Evelyn Trust Cambridge (Patrick Sisson's Research Fellowship) and the Karolinska Institutet (Jonas Söderquists Fellowship) awarded to I.P.F.; and the Foundation for Science and Technology of Portugal (FCT) scholarship (SFRH/BD/115612/2016) awarded to P.P.C. Conceptualization, I.P.F. and R.S.J.; methodology, I.P.F. P.P.C. E.S.-L. C.J. and R.S.J.; software, B.P.N. D.B. and C.J.; investigation, I.P.F. P.P.C. E.S.-L. E.A.M. A.G. C.J. S.K. N.D.Z. L.B. and D.N.; writing – original draft, I.P.F. and R.S.J.; writing – review & editing, all authors; funding acquisition, I.P.F. and R.S.J.; supervision, M.G. M.C.W. and R.S.J.; project administration, I.P.F. and R.S.J. The authors declare no competing interests. One or more of the authors of this paper self-identifies as a gender minority in their field of research. Funding Information: We thank Darren Cawkill, Mark Hoogenboezem, Ken G.C. Smith, and Pedro Velica for helpful comments and advice and Cristina M. Branco for recruitment and support of P.P.C.; the Cambridge NIHR BRC Cell Phenotyping Hub and the flow cytometry facility from the School of the Biological Sciences; and the animal caretakers of the NKI and the Sanquin FACS facility. This work was supported by Apollo Therapeutics, the Knut and Alice Wallenberg Scholar Award, the Swedish Medical Research Council (Vetenskapsrdet 2019-01485), the Swedish Cancer Fund (Cancerfonden, CAN2018/808), the Swedish Children’s Cancer Fund (Barncancerfonden PR2020-007), and the Wellcome Trust Principal Fellowship Award (214283/Z/18/Z) to R.S.J.; the Evelyn Trust Cambridge (Patrick Sisson’s Research Fellowship) and the Karolinska Institutet (Jonas Söderquists Fellowship) awarded to I.P.F.; and the Foundation for Science and Technology of Portugal (FCT) scholarship ( SFRH/BD/115612/2016 ) awarded to P.P.C. Publisher Copyright: © 2023

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.

KW - 2-hydroxyglutarate

KW - CD8+ T cell function

KW - CD8+ T cell memory

KW - CP: Immunology

KW - adoptive cell transfer

KW - oncometabolites

UR - http://www.scopus.com/inward/record.url?scp=85169330434&partnerID=8YFLogxK

U2 - https://doi.org/10.1016/j.celrep.2023.113013

DO - https://doi.org/10.1016/j.celrep.2023.113013

M3 - Article

C2 - 37632752

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

Abstract

Keywords

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