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Wagner A, Wang C, Fessler J, et al. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell. 2021;184(16):4168-4185.e21doi: 10.1016/j.cell.2021.05.045.
Wagner, A., Wang, C., Fessler, J., DeTomaso, D., Avila-Pacheco, J., Kaminski, J., Zaghouani, S., Christian, E., Thakore, P., Schellhaass, B., Akama-Garren, E., Pierce, K., Singh, V., Ron-Harel, N., Douglas, V. P., Bod, L., Schnell, A., Puleston, D., Sobel, R. A., Haigis, M., Pearce, E. L., Soleimani, M., Clish, C., Regev, A., Kuchroo, V. K., & Yosef, N. (2021). Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell, 184(16), 4168-4185.e21. https://doi.org/10.1016/j.cell.2021.05.045
Wagner, Allon, et al. "Metabolic modeling of single Th17 cells reveals regulators of autoimmunity." Cell vol. 184,16 (2021): 4168-4185.e21. doi: https://doi.org/10.1016/j.cell.2021.05.045
Wagner A, Wang C, Fessler J, DeTomaso D, Avila-Pacheco J, Kaminski J, Zaghouani S, Christian E, Thakore P, Schellhaass B, Akama-Garren E, Pierce K, Singh V, Ron-Harel N, Douglas VP, Bod L, Schnell A, Puleston D, Sobel RA, Haigis M, Pearce EL, Soleimani M, Clish C, Regev A, Kuchroo VK, Yosef N. Metabolic modeling of single Th17 cells reveals regulators of autoimmunity. Cell. 2021 Aug 05;184(16):4168-4185.e21. doi: 10.1016/j.cell.2021.05.045. Epub 2021 Jul 02. PMID: 34216539; PMCID: PMC8621950.
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Cell. 2021 Aug 05;184(16):4168-4185.e21. doi: 10.1016/j.cell.2021.05.045. Epub 2021 Jul 02.

Metabolic modeling of single Th17 cells reveals regulators of autoimmunity.

Cell

Allon Wagner, Chao Wang, Johannes Fessler, David DeTomaso, Julian Avila-Pacheco, James Kaminski, Sarah Zaghouani, Elena Christian, Pratiksha Thakore, Brandon Schellhaass, Elliot Akama-Garren, Kerry Pierce, Vasundhara Singh, Noga Ron-Harel, Vivian Paraskevi Douglas, Lloyd Bod, Alexandra Schnell, Daniel Puleston, Raymond A Sobel, Marcia Haigis, Erika L Pearce, Manoocher Soleimani, Clary Clish, Aviv Regev, Vijay K Kuchroo, Nir Yosef

Affiliations

  1. Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  2. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Biological Sciences Platform, Sunnybrook Research Institute, Toronto, ON M4N 3M5, Canada; Department of Immunology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
  3. Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA.
  4. Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA.
  5. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
  6. Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA.
  7. Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Department of Biology, Technion, Israel Institute of Technology, Haifa 3200003, Israel.
  8. Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA.
  9. Max Planck Institute of Immunobiology and Epigenetics, 79108 Freiburg, Germany.
  10. Palo Alto Veteran's Administration Health Care System and Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.
  11. Department of Cell Biology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
  12. Department of Medicine, University of New Mexico Health Sciences Center, Albuquerque, NM 87121, USA.
  13. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, MA 02140, USA.
  14. Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. Electronic address: [email protected].
  15. Department of Electrical Engineering and Computer Science, University of California, Berkeley, Berkeley, CA 94720, USA; Center for Computational Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Chan-Zuckerberg Biohub, San Francisco, CA 94158, USA; Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA. Electronic address: [email protected].

PMID: 34216539 PMCID: PMC8621950 DOI: 10.1016/j.cell.2021.05.045

Abstract

Metabolism is a major regulator of immune cell function, but it remains difficult to study the metabolic status of individual cells. Here, we present Compass, an algorithm to characterize cellular metabolic states based on single-cell RNA sequencing and flux balance analysis. We applied Compass to associate metabolic states with T helper 17 (Th17) functional variability (pathogenic potential) and recovered a metabolic switch between glycolysis and fatty acid oxidation, akin to known Th17/regulatory T cell (Treg) differences, which we validated by metabolic assays. Compass also predicted that Th17 pathogenicity was associated with arginine and downstream polyamine metabolism. Indeed, polyamine-related enzyme expression was enhanced in pathogenic Th17 and suppressed in Treg cells. Chemical and genetic perturbation of polyamine metabolism inhibited Th17 cytokines, promoted Foxp3 expression, and remodeled the transcriptome and epigenome of Th17 cells toward a Treg-like state. In vivo perturbations of the polyamine pathway altered the phenotype of encephalitogenic T cells and attenuated tissue inflammation in CNS autoimmunity.

Copyright © 2021 Elsevier Inc. All rights reserved.

Keywords: DFMO; T helper 17 cell; experimental autoimmune encephalomyelitis; immunometabolism; in silico metabolic modeling; multiple sclerosis; polyamines; putrescine; single cell transcriptomics; spermidine

Conflict of interest statement

Declaration of interests V.K.K. has an ownership interest and is a member of the SAB for Tizona Therapeutics and is a co-founder of and has an ownership interest in Celsius Therapeutics. V.K.K. is an

References

  1. Cell. 2018 Dec 13;175(7):1780-1795.e19 - PubMed
  2. Nucleic Acids Res. 2015 Apr 20;43(7):e47 - PubMed
  3. Nat Biotechnol. 2013 May;31(5):419-25 - PubMed
  4. Immunol Res. 2011 Aug;50(2-3):181-7 - PubMed
  5. Nat Commun. 2019 Sep 26;10(1):4376 - PubMed
  6. J Clin Immunol. 2014 Jul;34 Suppl 1:S56-60 - PubMed
  7. Curr Opin Immunol. 2017 Jun;46:38-44 - PubMed
  8. Nat Immunol. 2012 Oct;13(10):991-9 - PubMed
  9. Nature. 2006 May 11;441(7090):235-8 - PubMed
  10. J Exp Med. 2014 Sep 22;211(10):2075-84 - PubMed
  11. Cell. 2012 Oct 12;151(2):289-303 - PubMed
  12. Immunity. 2006 Feb;24(2):179-89 - PubMed
  13. Elife. 2017 Dec 05;6: - PubMed
  14. Immunity. 2014 Apr 17;40(4):477-89 - PubMed
  15. J Biol Chem. 2007 Mar 16;282(11):8404-13 - PubMed
  16. J Clin Invest. 2015 Jan;125(1):194-207 - PubMed
  17. Immunol Rev. 2013 Mar;252(1):52-77 - PubMed
  18. J Mol Cell Biol. 2015 Dec;7(6):505-16 - PubMed
  19. Front Immunol. 2013 Apr 17;4:91 - PubMed
  20. Nat Rev Immunol. 2019 May;19(5):291-304 - PubMed
  21. Bioinformatics. 2011 Apr 1;27(7):1017-8 - PubMed
  22. Nat Med. 2014 Nov;20(11):1327-33 - PubMed
  23. Pediatr Res. 2009 May;65(5 Pt 2):26R-31R - PubMed
  24. J Immunol. 2009 Dec 1;183(11):7169-77 - PubMed
  25. Immunity. 2015 Mar 17;42(3):419-30 - PubMed
  26. PLoS Comput Biol. 2008 May 16;4(5):e1000082 - PubMed
  27. Nat Rev Immunol. 2011 Apr;11(4):275-88 - PubMed
  28. Immunol Rev. 2020 May;295(1):5-14 - PubMed
  29. Cell Syst. 2019 Apr 24;8(4):315-328.e8 - PubMed
  30. Bioinformatics. 2014 Aug 1;30(15):2114-20 - PubMed
  31. Genome Biol. 2014;15(12):550 - PubMed
  32. Genome Res. 2005 Aug;15(8):1034-50 - PubMed
  33. Nat Biotechnol. 2016 May;34(5):525-7 - PubMed
  34. Cell Syst. 2019 Jan 23;8(1):43-52.e5 - PubMed
  35. Arthritis Rheum. 2012 Jun;64(6):1809-17 - PubMed
  36. Nucleic Acids Res. 2018 Jan 4;46(D1):D1284 - PubMed
  37. Nat Biotechnol. 2016 Nov 8;34(11):1145-1160 - PubMed
  38. Cell Metab. 2017 Jul 5;26(1):131-141 - PubMed
  39. Nat Cell Biol. 2019 Jan;21(1):85-93 - PubMed
  40. Nat Immunol. 2007 Dec;8(12):1390-7 - PubMed
  41. Nat Protoc. 2019 Mar;14(3):639-702 - PubMed
  42. Cell Host Microbe. 2016 Aug 10;20(2):167-77 - PubMed
  43. Nat Genet. 2016 Oct;48(10):1193-203 - PubMed
  44. Cell. 2018 Jul 26;174(3):716-729.e27 - PubMed
  45. J Exp Med. 2011 Jul 4;208(7):1367-76 - PubMed
  46. Immunity. 2021 Jan 12;54(1):19-31 - PubMed
  47. Immunity. 2008 Apr;28(4):445-53 - PubMed
  48. Nucleic Acids Res. 2016 Jan 4;44(D1):D126-32 - PubMed
  49. Nature. 2003 Feb 13;421(6924):744-8 - PubMed
  50. Nat Metab. 2021 Jan;3(1):21-32 - PubMed
  51. Autoimmunity. 1994;19(4):253-64 - PubMed
  52. Nat Rev Cancer. 2018 Nov;18(11):681-695 - PubMed
  53. Nat Commun. 2014 Dec 22;5:5780 - PubMed
  54. Cell. 2015 Dec 3;163(6):1400-12 - PubMed
  55. Front Immunol. 2015 Dec 17;6:639 - PubMed
  56. Nature. 2014 Jun 5;510(7503):152-6 - PubMed
  57. Nucleic Acids Res. 2017 Jan 4;45(D1):D353-D361 - PubMed
  58. Nature. 2006 May 11;441(7090):231-4 - PubMed
  59. Am J Physiol Endocrinol Metab. 2008 Jun;294(6):E995-1010 - PubMed
  60. Immunity. 2019 Feb 19;50(2):493-504.e7 - PubMed
  61. Cell Metab. 2018 Sep 4;28(3):490-503.e7 - PubMed
  62. Genome Biol. 2019 Oct 11;20(1):206 - PubMed
  63. Cell. 2015 Dec 3;163(6):1413-27 - PubMed
  64. mSystems. 2018 Mar 27;3(3): - PubMed
  65. Cell Metab. 2020 Dec 1;32(6):908-919 - PubMed
  66. Immunopharmacology. 1987 Apr;13(2):143-7 - PubMed
  67. Nat Rev Genet. 2014 Feb;15(2):107-20 - PubMed
  68. Mol Syst Biol. 2010 Jul;6:390 - PubMed
  69. Nat Methods. 2013 Dec;10(12):1213-8 - PubMed
  70. Cell. 2017 May 4;169(4):570-586 - PubMed
  71. Nat Rev Microbiol. 2012 Feb 27;10(4):291-305 - PubMed
  72. Nat Biotechnol. 2018 Jun;36(5):421-427 - PubMed
  73. Genome Biol. 2008;9(9):R137 - PubMed
  74. Genome Biol. 2014 Feb 03;15(2):R29 - PubMed
  75. Nat Methods. 2012 Mar 04;9(4):357-9 - PubMed
  76. Immunity. 2017 Sep 19;47(3):406-420 - PubMed
  77. Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50 - PubMed
  78. Nat Biotechnol. 2008 Sep;26(9):1003-10 - PubMed
  79. Nat Rev Immunol. 2021 Mar;21(3):151-161 - PubMed
  80. J Immunol. 2011 Mar 15;186(6):3299-303 - PubMed
  81. Nat Rev Immunol. 2016 Sep;16(9):553-65 - PubMed
  82. Annu Rev Immunol. 2009;27:485-517 - PubMed
  83. mBio. 2019 Mar 26;10(2): - PubMed
  84. Trends Cell Biol. 2014 May;24(5):313-20 - PubMed
  85. Annu Rev Immunol. 2018 Apr 26;36:461-488 - PubMed
  86. Genome Biol. 2016 Apr 27;17:75 - PubMed
  87. Nat Biotechnol. 2010 May;28(5):495-501 - PubMed
  88. J Clin Invest. 2021 Jan 19;131(2): - PubMed
  89. Nature. 2013 Apr 25;496(7446):461-8 - PubMed
  90. Curr Opin HIV AIDS. 2010 Mar;5(2):120-7 - PubMed
  91. Immunity. 2009 Apr 17;30(4):576-87 - PubMed
  92. Cell Metab. 2018 Sep 4;28(3):504-515.e7 - PubMed
  93. Nat Methods. 2018 Jul;15(7):539-542 - PubMed
  94. Immunity. 2008 Apr;28(4):454-67 - PubMed
  95. Nature. 2008 Jun 19;453(7198):1051-7 - PubMed
  96. Nat Biotechnol. 2010 Mar;28(3):245-8 - PubMed
  97. Nat Immunol. 2009 Mar;10(3):314-24 - PubMed
  98. Cell. 2015 May 21;161(5):971-987 - PubMed
  99. Science. 2009 Jun 5;324(5932):1334-8 - PubMed
  100. Nat Biotechnol. 2014 May;32(5):447-52 - PubMed
  101. Nat Methods. 2020 Jan;17(1):45-49 - PubMed
  102. PLoS Comput Biol. 2019 Feb 28;15(2):e1006733 - PubMed
  103. J Immunol. 2009 May 15;182(10):5904-8 - PubMed
  104. Nature. 2010 Oct 21;467(7318):967-71 - PubMed
  105. Biophys J. 2011 Feb 2;100(3):544-553 - PubMed
  106. Cell Metab. 2019 Dec 3;30(6):1055-1074.e8 - PubMed
  107. Cell. 2016 Oct 6;167(2):457-470.e13 - PubMed
  108. Nature. 2012 Apr 26;484(7395):514-8 - PubMed

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