Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK during T lymphocyte activation.
Activation of a naive T cell is a highly energetic event, which requires a substantial increase in nutrient metabolism. Upon stimulation, T cells increase in size, rapidly proliferate, and differentiate, all of which lead to a high demand for energetic and biosynthetic precursors. Although amino acids are the basic building blocks of protein biosynthesis and contribute to many other metabolic processes, the role of amino acid metabolism in T cell activation has not been well characterized. We have found that glutamine in particular is required for T cell function. Depletion of glutamine blocks proliferation and cytokine production, and this cannot be rescued by supplying biosynthetic precursors of glutamine. Correlating with the absolute requirement for glutamine, T cell activation induces a large increase in glutamine import, but not glutamate import, and this increase is CD28-dependent. Activation coordinately enhances expression of glutamine transporters and activities of enzymes required to allow the use of glutamine as a Krebs cycle substrate in T cells. The induction of glutamine uptake and metabolism requires ERK function, providing a link to TCR signaling. Together, these data indicate that regulation of glutamine use is an important component of T cell activation. Thus, a better understanding of glutamine sensing and use in T cells may reveal novel targets for immunomodulation.
Carr
Erikka L
EL
Department of Cell Biology and Molecular Genetics, Maryland Pathogen Research Institute, University of Maryland, College Park, MD 20742, USA.
Kelman
Alina
A
Wu
Glendon S
GS
Gopaul
Ravindra
R
Senkevitch
Emilee
E
Aghvanyan
Anahit
A
Turay
Achmed M
AM
Frauwirth
Kenneth A
KA
D000410:Alanine Transaminase / Q000378:metabolism; D026924:Amino Acid Transport System A / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001219:Aspartate Aminotransferases / Q000378:metabolism; D001692:Biological Transport / Q000187:drug effects; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005419:Flavonoids / Q000494:pharmacology; D005434:Flow Cytometry; D005969:Glutamate Dehydrogenase / Q000378:metabolism; D005972:Glutaminase / Q000235:genetics / Q000378:metabolism; D005973:Glutamine / Q000378:metabolism* / Q000493:pharmacokinetics / Q000494:pharmacology; D007656:Ketoglutaric Acids / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D020935:MAP Kinase Signaling System / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism
D026924:Amino Acid Transport System A; D005419:Flavonoids; D007656:Ketoglutaric Acids; C498798:Slc38a2 protein, mouse; D005973:Glutamine; D005969:Glutamate Dehydrogenase; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase; D048049:Extracellular Signal-Regulated MAP Kinases; D005972:Glutaminase; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one