Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways

Partho Sen; Syed Bilal Ahmad Andrabi; Tanja Buchacher; Mohd Moin Khan; Ubaid Ullah Kalim; Tuomas Mikael Lindeman; Marina Amaral Alves; Victoria Hinkkanen; Esko Kemppainen; Alex M. Dickens; Omid Rasool; Tuulia Hyötyläinen; Riitta Lahesmaa; Matej Orešič

doi:10.1016/j.celrep.2021.109973

Quantitative genome-scale metabolic modeling of human CD4⁺ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways

Partho Sen^*
, Syed Bilal Ahmad Andrabi
, Tanja Buchacher
, Mohd Moin Khan
, Ubaid Ullah Kalim
, Tuomas Mikael Lindeman
, Marina Amaral Alves
, Victoria Hinkkanen
, Esko Kemppainen
, Alex M. Dickens
, Omid Rasool
, Tuulia Hyötyläinen
, Riitta Lahesmaa
, Matej Orešič

^*Korresponderande författare för detta arbete

Åbo biovetenskapscentrum

Forskningsoutput: Tidskriftsbidrag › Artikel › Vetenskaplig › Peer review

21 Citeringar (Scopus)

Sammanfattning

T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4⁺ T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4⁺ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4⁺ T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.

Originalspråk	Engelska
Artikelnummer	109973
Tidskrift	Cell Reports
Volym	37
Nummer	6
DOI	https://doi.org/10.1016/j.celrep.2021.109973
Status	Publicerad - 9 nov. 2021
MoE-publikationstyp	A1 Tidskriftsartikel-refererad

Finansiering

We thank Marjo Hakkarinen and Sarita Heinonen (Turku Bioscience Center, University of Turku, Turku, Finland) for excellent technical assistance. We would like to acknowledge the Turku Metabolomics Centre and Biocenter Finland for their contribution to metabolomic analysis. We thank Dr. Aidan McGlinchey (School of Medical Sciences, ?rebro University, ?rebro, Sweden) for assistance with editing the manuscript. This study was supported by the Novo Nordisk Foundation (NNF18OC0034506 and NNF19OC0057418 to M.O.), the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) (no. 250114 to M.O. and R.L.), the Academy of Finland (no. 333981 to M.O. and nos. 292335, 294337, and 319280 to R.L.), the Sigrid Jus?lius Foundation (to R.L.), the Jane and Aatos Erkko Foundation (to R.L.), the Finnish Cancer Foundation (to R.L.), and the Juvenile Diabetes Research Foundation (2-SRA-2014-159-Q-R to M.O). M.O. proposed the study. R.L. and M.O. supervised the study. P.S. U.U. R.L. and M.O. assisted with the formulation of study design. P.S. performed GSMM and analyzed the multi-omics datasets. T.H. and A.D. supervised the metabolomics experiments. T.L. M.A. A.M.D. and T.H. acquired the metabolomics data. E.K. V.H. S.B.A.A. T.B. M.M.K. and O.R. prepared and provided CD4+ T cell subsets for metabolomics experiments. S.B.A.A. and T.B. performed the siRNA knockdown experiments. P.S. and M.O. wrote the manuscript. All authors critically reviewed and approved the final manuscript. M.O. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors declare no competing interests. We thank Marjo Hakkarinen and Sarita Heinonen (Turku Bioscience Center, University of Turku, Turku, Finland) for excellent technical assistance. We would like to acknowledge the Turku Metabolomics Centre and Biocenter Finland for their contribution to metabolomic analysis. We thank Dr. Aidan McGlinchey (School of Medical Sciences, Örebro University, Örebro, Sweden) for assistance with editing the manuscript. This study was supported by the Novo Nordisk Foundation ( NNF18OC0034506 and NNF19OC0057418 to M.O.), the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) (no. 250114 to M.O. and R.L.), the Academy of Finland (no. 333981 to M.O. and nos. 292335 , 294337 , and 319280 to R.L.), the Sigrid Jusélius Foundation (to R.L.), the Jane and Aatos Erkko Foundation (to R.L.), the Finnish Cancer Foundation (to R.L.), and the Juvenile Diabetes Research Foundation ( 2-SRA-2014-159-Q-R to M.O).

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Sen, P., Andrabi, S. B. A., Buchacher, T., Khan, M. M., Kalim, U. U., Lindeman, T. M., Alves, M. A., Hinkkanen, V., Kemppainen, E., Dickens, A. M., Rasool, O., Hyötyläinen, T., Lahesmaa, R., & Orešič, M. (2021). Quantitative genome-scale metabolic modeling of human CD4⁺ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways. Cell Reports, 37(6), Artikel 109973. https://doi.org/10.1016/j.celrep.2021.109973

@article{fe435bdbf28d4241bb5d9c6a87cffcb1,

title = "Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways",

abstract = "T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4+ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4+ T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.",

keywords = "CD4 T cells, ceramides, gene expression, genome-scale metabolic modeling, glycosphingolipid metabolism, lipid metabolism, lipidomics, metabolic pathways, sphingolipids, type 1 diabetes",

author = "Partho Sen and Andrabi, \{Syed Bilal Ahmad\} and Tanja Buchacher and Khan, \{Mohd Moin\} and Kalim, \{Ubaid Ullah\} and Lindeman, \{Tuomas Mikael\} and Alves, \{Marina Amaral\} and Victoria Hinkkanen and Esko Kemppainen and Dickens, \{Alex M.\} and Omid Rasool and Tuulia Hy{\"o}tyl{\"a}inen and Riitta Lahesmaa and Matej Ore{\v s}i{\v c}",

note = "Funding Information: We thank Marjo Hakkarinen and Sarita Heinonen (Turku Bioscience Center, University of Turku, Turku, Finland) for excellent technical assistance. We would like to acknowledge the Turku Metabolomics Centre and Biocenter Finland for their contribution to metabolomic analysis. We thank Dr. Aidan McGlinchey (School of Medical Sciences, ?rebro University, ?rebro, Sweden) for assistance with editing the manuscript. This study was supported by the Novo Nordisk Foundation (NNF18OC0034506 and NNF19OC0057418 to M.O.), the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) (no. 250114 to M.O. and R.L.), the Academy of Finland (no. 333981 to M.O. and nos. 292335, 294337, and 319280 to R.L.), the Sigrid Jus?lius Foundation (to R.L.), the Jane and Aatos Erkko Foundation (to R.L.), the Finnish Cancer Foundation (to R.L.), and the Juvenile Diabetes Research Foundation (2-SRA-2014-159-Q-R to M.O). M.O. proposed the study. R.L. and M.O. supervised the study. P.S. U.U. R.L. and M.O. assisted with the formulation of study design. P.S. performed GSMM and analyzed the multi-omics datasets. T.H. and A.D. supervised the metabolomics experiments. T.L. M.A. A.M.D. and T.H. acquired the metabolomics data. E.K. V.H. S.B.A.A. T.B. M.M.K. and O.R. prepared and provided CD4+ T cell subsets for metabolomics experiments. S.B.A.A. and T.B. performed the siRNA knockdown experiments. P.S. and M.O. wrote the manuscript. All authors critically reviewed and approved the final manuscript. M.O. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors declare no competing interests. Funding Information: We thank Marjo Hakkarinen and Sarita Heinonen (Turku Bioscience Center, University of Turku, Turku, Finland) for excellent technical assistance. We would like to acknowledge the Turku Metabolomics Centre and Biocenter Finland for their contribution to metabolomic analysis. We thank Dr. Aidan McGlinchey (School of Medical Sciences, {\"O}rebro University, {\"O}rebro, Sweden) for assistance with editing the manuscript. This study was supported by the Novo Nordisk Foundation ( NNF18OC0034506 and NNF19OC0057418 to M.O.), the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) (no. 250114 to M.O. and R.L.), the Academy of Finland (no. 333981 to M.O. and nos. 292335 , 294337 , and 319280 to R.L.), the Sigrid Jus{\'e}lius Foundation (to R.L.), the Jane and Aatos Erkko Foundation (to R.L.), the Finnish Cancer Foundation (to R.L.), and the Juvenile Diabetes Research Foundation ( 2-SRA-2014-159-Q-R to M.O). Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = nov,

day = "9",

doi = "10.1016/j.celrep.2021.109973",

language = "English",

volume = "37",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Cell Press",

number = "6",

}

Sen, P, Andrabi, SBA, Buchacher, T, Khan, MM, Kalim, UU, Lindeman, TM, Alves, MA, Hinkkanen, V, Kemppainen, E, Dickens, AM, Rasool, O, Hyötyläinen, T, Lahesmaa, R & Orešič, M 2021, 'Quantitative genome-scale metabolic modeling of human CD4⁺ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways', Cell Reports, vol. 37, nr. 6, 109973. https://doi.org/10.1016/j.celrep.2021.109973

TY - JOUR

T1 - Quantitative genome-scale metabolic modeling of human CD4+ T cell differentiation reveals subset-specific regulation of glycosphingolipid pathways

AU - Sen, Partho

AU - Andrabi, Syed Bilal Ahmad

AU - Buchacher, Tanja

AU - Khan, Mohd Moin

AU - Kalim, Ubaid Ullah

AU - Lindeman, Tuomas Mikael

AU - Alves, Marina Amaral

AU - Hinkkanen, Victoria

AU - Kemppainen, Esko

AU - Dickens, Alex M.

AU - Rasool, Omid

AU - Hyötyläinen, Tuulia

AU - Lahesmaa, Riitta

AU - Orešič, Matej

N1 - Funding Information: We thank Marjo Hakkarinen and Sarita Heinonen (Turku Bioscience Center, University of Turku, Turku, Finland) for excellent technical assistance. We would like to acknowledge the Turku Metabolomics Centre and Biocenter Finland for their contribution to metabolomic analysis. We thank Dr. Aidan McGlinchey (School of Medical Sciences, ?rebro University, ?rebro, Sweden) for assistance with editing the manuscript. This study was supported by the Novo Nordisk Foundation (NNF18OC0034506 and NNF19OC0057418 to M.O.), the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) (no. 250114 to M.O. and R.L.), the Academy of Finland (no. 333981 to M.O. and nos. 292335, 294337, and 319280 to R.L.), the Sigrid Jus?lius Foundation (to R.L.), the Jane and Aatos Erkko Foundation (to R.L.), the Finnish Cancer Foundation (to R.L.), and the Juvenile Diabetes Research Foundation (2-SRA-2014-159-Q-R to M.O). M.O. proposed the study. R.L. and M.O. supervised the study. P.S. U.U. R.L. and M.O. assisted with the formulation of study design. P.S. performed GSMM and analyzed the multi-omics datasets. T.H. and A.D. supervised the metabolomics experiments. T.L. M.A. A.M.D. and T.H. acquired the metabolomics data. E.K. V.H. S.B.A.A. T.B. M.M.K. and O.R. prepared and provided CD4+ T cell subsets for metabolomics experiments. S.B.A.A. and T.B. performed the siRNA knockdown experiments. P.S. and M.O. wrote the manuscript. All authors critically reviewed and approved the final manuscript. M.O. is the guarantor of this work and, as such, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors declare no competing interests. Funding Information: We thank Marjo Hakkarinen and Sarita Heinonen (Turku Bioscience Center, University of Turku, Turku, Finland) for excellent technical assistance. We would like to acknowledge the Turku Metabolomics Centre and Biocenter Finland for their contribution to metabolomic analysis. We thank Dr. Aidan McGlinchey (School of Medical Sciences, Örebro University, Örebro, Sweden) for assistance with editing the manuscript. This study was supported by the Novo Nordisk Foundation ( NNF18OC0034506 and NNF19OC0057418 to M.O.), the Academy of Finland Centre of Excellence in Molecular Systems Immunology and Physiology Research (SyMMyS) (no. 250114 to M.O. and R.L.), the Academy of Finland (no. 333981 to M.O. and nos. 292335 , 294337 , and 319280 to R.L.), the Sigrid Jusélius Foundation (to R.L.), the Jane and Aatos Erkko Foundation (to R.L.), the Finnish Cancer Foundation (to R.L.), and the Juvenile Diabetes Research Foundation ( 2-SRA-2014-159-Q-R to M.O). Publisher Copyright: © 2021 The Author(s)

PY - 2021/11/9

Y1 - 2021/11/9

N2 - T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4+ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4+ T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.

AB - T cell activation, proliferation, and differentiation involve metabolic reprogramming resulting from the interplay of genes, proteins, and metabolites. Here, we aim to understand the metabolic pathways involved in the activation and functional differentiation of human CD4+ T cell subsets (T helper [Th]1, Th2, Th17, and induced regulatory T [iTreg] cells). Here, we combine genome-scale metabolic modeling, gene expression data, and targeted and non-targeted lipidomics experiments, together with in vitro gene knockdown experiments, and show that human CD4+ T cells undergo specific metabolic changes during activation and functional differentiation. In addition, we confirm the importance of ceramide and glycosphingolipid biosynthesis pathways in Th17 differentiation and effector functions. Through in vitro gene knockdown experiments, we substantiate the requirement of serine palmitoyltransferase (SPT), a de novo sphingolipid pathway in the expression of proinflammatory cytokines (interleukin [IL]-17A and IL17F) by Th17 cells. Our findings provide a comprehensive resource for selective manipulation of CD4+ T cells under disease conditions characterized by an imbalance of Th17/natural Treg (nTreg) cells.

KW - CD4 T cells

KW - ceramides

KW - gene expression

KW - genome-scale metabolic modeling

KW - glycosphingolipid metabolism

KW - lipid metabolism

KW - lipidomics

KW - metabolic pathways

KW - sphingolipids

KW - type 1 diabetes

UR - https://www.scopus.com/pages/publications/85118862025

U2 - 10.1016/j.celrep.2021.109973

DO - 10.1016/j.celrep.2021.109973

M3 - Article

C2 - 34758307

AN - SCOPUS:85118862025

SN - 2211-1247

VL - 37

JO - Cell Reports

JF - Cell Reports

IS - 6

M1 - 109973

ER -