title: Control of amino-acid transport by antigen receptors coordinates the metabolic reprogramming essential for T cell differentiation.
abstract: T lymphocytes must regulate nutrient uptake to meet the metabolic demands of an immune response. Here we show that the intracellular supply of large neutral amino acids (LNAAs) in T cells was regulated by pathogens and the T cell antigen receptor (TCR). T cells responded to antigen by upregulating expression of many amino-acid transporters, but a single System L ('leucine-preferring system') transporter, Slc7a5, mediated uptake of LNAAs in activated T cells. Slc7a5-null T cells were unable to metabolically reprogram in response to antigen and did not undergo clonal expansion or effector differentiation. The metabolic catastrophe caused by loss of Slc7a5 reflected the requirement for sustained uptake of the LNAA leucine for activation of the serine-threonine kinase complex mTORC1 and for expression of the transcription factor c-Myc. Control of expression of the System L transporter by pathogens is thus a critical metabolic checkpoint for T cells.
authors.affiliation: Division of Cell Signalling and Immunology, University of Dundee, Dundee, UK.
authors.forename: Linda V
authors.initials: LV
authors.lastname: Sinclair
authors.forename: Julia
authors.initials: J
authors.lastname: Rolf
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Emslie
authors.forename: Yun-Bo
authors.initials: YB
authors.lastname: Shi
authors.forename: Peter M
authors.initials: PM
authors.lastname: Taylor
authors.forename: Doreen A
authors.initials: DA
authors.lastname: Cantrell
mesh_terms: D021542:Amino Acids, Neutral / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D021381:Protein Transport; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D015854:Up-Regulation
chemical_list: D021542:Amino Acids, Neutral; D007376:Interleukin-2; D027283:Large Neutral Amino Acid-Transporter 1; D016693:Receptors, Antigen, T-Cell, alpha-beta; D007371:Interferon-gamma