Editors' ChoiceImmunometabolism

Fueling T cell biology

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Science Signaling  21 Jun 2016:
Vol. 9, Issue 433, pp. ec143
DOI: 10.1126/scisignal.aag3262

To support the protein synthesis and energy requirements for activation and proliferation, T cells increase their uptake of nutrients, including glucose and glutamine. These nutrients also feed into the hexosamine biosynthetic pathway to generate UDP-GlcNAc, the substrate for the enzyme O-GlcNAc transferase (OGT), which catalyzes the reversible posttranslational modification of proteins on serines or threonines called O-GlcNAcylation. Swamy et al. found that T cell receptor (TCR)–stimulated mouse T cells had increased amounts of glucose and glutamine transporters compared with those of unstimulated cells, as well as increased intracellular concentrations of UDP-GlcNAc. Western blotting and flow cytometric analyses showed that TCR-stimulated T cells had increased amounts of O-GlcNAcylated proteins compared with those of naïve T cells, a response that preceded the cell growth and entry into the cell cycle that are required for T cell activation. Through experiments with a series of mice with conditional or inducible knockout of the gene encoding OGT at different stages of T cell development, the authors showed that OGT was required for (i) the Notch-dependent self-renewal of double-negative thymocytes; (ii) the transition of CD4 and CD8 double-positive thymocytes to CD4 or CD8 single-positive thymocytes and mature T cells; and (iii) the TCR-stimulated proliferation of cytotoxic T cells (CTLs) in response to interleukin-2. Knockout of the gene encoding the phosphatase PTEN in thymocytes leads to T cell acute lymphoblastic leukemia in mice; however, knockout of Ogt in Pten-deficient thymocytes prevented their malignant transformation. Inducible knockout of Ogt in CTLs reduced the abundance of c-Myc protein, whereas TCR stimulation of T cells treated with an inhibitor of the enzyme that removes O-GlcNAc moieties from proteins increased c-Myc abundance. Western blotting analysis showed that c-Myc was indeed O-GlcNAcylated in T cells. In response to TCR stimulation, c-Myc induces the expression of genes encoding glucose and glutamine transporters. Whereas TCR-stimulated wild-type CD4+ T cells exhibited enhanced protein O-GlcNAcylation, TCR-stimulated c-Myc‑deficient CD4+ T cells did not. Together, these data suggest that glucose and glutamine stimulate the O-GlcNAcylation of proteins, such as c-Myc, in a feedback loop to drive T cell renewal, proliferation, and transformation. As Yang and Marth discuss, these findings suggest that protein O-GlcNAcylation reports on the metabolic state of the cell and may contribute to a type of “metabolic checkpoint.”

M. Swamy, S. Pathak, K. M. Grzes, S. Damerow, L. V. Sinclair, D. M. F. van Aalten, D. A. Cantrell, Glucose and glutamine fuel protein O-GlcNAcylation to control T cell self-renewal and malignancy. Nat. Immunol. 17, 712–720 (2016). [PubMed]

W. H. Yang, J. D. Marth, Protein glycosylation energizes T cells. Nat. Immunol. 17, 613–614 (2016). [PubMed]

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