title: LAT1 is a critical transporter of essential amino acids for immune reactions in activated human T cells.
abstract: Activation of T cells accompanies remarkable enhancement of metabolism. Sufficient and continuous nutrient supply is therefore important to support immune reaction in T cells. However, the mechanism of the promotion of nutrient incorporation in activated T cells has not been elucidated. In this study, we show that L-type amino acid transporter 1 (LAT1) is a major transporter for essential amino acids into activated human T cells. CD3/CD28 stimulation in primary human T cells triggered dramatic induction of LAT1 expression mediated by NF-κB and AP-1. Functional disturbance of LAT1 by a specific inhibitor and by small interfering RNA in human T cells suppressed essential amino acid uptake and induced a stress response mediated by DNA damage-inducible transcript 3 to attenuate cytokine production via inhibition of NF-κB and NFAT activities. These results uncover the previously unknown mechanism by which T cells accelerate essential amino acid uptake upon activation and adapt to essential amino acid starvation. Our results also raise the possibility for application of an LAT1 inhibitor as a new drug for therapy of disease caused by exaggerated immune response.
authors.affiliation: Department of Pharmacology and Toxicology, Dokkyo Medical University School of Medicine, Tochigi 321-0293, Japan;
authors.forename: Keitaro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Promsuk
authors.initials: P
authors.lastname: Jutabha
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Endou
authors.forename: Hironori
authors.initials: H
authors.lastname: Sagara
authors.forename: Naohiko
authors.initials: N
authors.lastname: Anzai
mesh_terms: D026905:Amino Acid Transport Systems; D000601:Amino Acids, Essential / Q000378:metabolism*; D001692:Biological Transport; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D002478:Cells, Cultured; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics / Q000378:metabolism*; D008213:Lymphocyte Activation; D016328:NF-kappa B / Q000378:metabolism; D050778:NFATC Transcription Factors / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D051742:Transcription Factor CHOP / Q000378:metabolism
chemical_list: D026905:Amino Acid Transport Systems; D000601:Amino Acids, Essential; D018106:CD28 Antigens; D017252:CD3 Complex; D027283:Large Neutral Amino Acid-Transporter 1; D016328:NF-kappa B; D050778:NFATC Transcription Factors; D034741:RNA, Small Interfering; D018808:Transcription Factor AP-1; D051742:Transcription Factor CHOP