Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy

Nat Immunol. 2016 Jun;17(6):712-20. doi: 10.1038/ni.3439. Epub 2016 Apr 25.


Sustained glucose and glutamine transport are essential for activated T lymphocytes to support ATP and macromolecule biosynthesis. We found that glutamine and glucose also fuel an indispensable dynamic regulation of intracellular protein O-GlcNAcylation at key stages of T cell development, transformation and differentiation. Glucose and glutamine are precursors of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc), a substrate for cellular glycosyltransferases. Immune-activated T cells contained higher concentrations of UDP-GlcNAc and increased intracellular protein O-GlcNAcylation controlled by the enzyme O-linked-β-N-acetylglucosamine (O-GlcNAc) glycosyltransferase as compared with naive cells. We identified Notch, the T cell antigen receptor and c-Myc as key controllers of T cell protein O-GlcNAcylation via regulation of glucose and glutamine transport. Loss of O-GlcNAc transferase blocked T cell progenitor renewal, malignant transformation and peripheral T cell clonal expansion. Nutrient-dependent signaling pathways regulated by O-GlcNAc glycosyltransferase are thus fundamental for T cell biology.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Proliferation / genetics
  • Cell Self Renewal / genetics
  • Cell Transformation, Neoplastic / genetics
  • Clone Cells
  • Female
  • Glucose / metabolism*
  • Glutamine / metabolism*
  • Lymphocyte Activation / genetics
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • N-Acetylglucosaminyltransferases / genetics
  • N-Acetylglucosaminyltransferases / metabolism*
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Receptors, Antigen, T-Cell / metabolism*
  • Receptors, Notch / metabolism
  • T-Lymphocytes / physiology*
  • Uridine Diphosphate N-Acetylglucosamine / metabolism*


  • Myc protein, mouse
  • Proto-Oncogene Proteins c-myc
  • Receptors, Antigen, T-Cell
  • Receptors, Notch
  • Glutamine
  • Uridine Diphosphate N-Acetylglucosamine
  • N-Acetylglucosaminyltransferases
  • Lymphocyte Specific Protein Tyrosine Kinase p56(lck)
  • Glucose