title: TCR engagement increases hypoxia-inducible factor-1 alpha protein synthesis via rapamycin-sensitive pathway under hypoxic conditions in human peripheral T cells.
abstract: Peripheral T cells encounter rapid decrease in oxygen tension because they are activated by Ag recognition and migrate into inflammatory sites or tumors. Activated T cells, therefore, are thought to have such machineries that enable them to adapt to hypoxic conditions and execute immune regulation in situ. We have recently shown that survival of CD3-engaged human peripheral blood T cells is prolonged under hypoxic conditions and hypoxia-inducible factor-1 (HIF-1) and its target gene product adrenomedullin play a critical role for the process. It is also shown that hypoxia alone is not sufficient, but TCR-mediated signal is required for accumulation of HIF-1alpha in human peripheral T cells. In the present study, we showed that TCR engagement does not influence hypoxia-dependent stabilization but stimulates protein synthesis of HIF-1alpha, most possibly via PI3K/mammalian target of rapamycin system, and that expression of HIF-1alpha and its target genes is blocked by treatment with rapamycin. Since some of those gene products, e.g., glucose transporters and phosphoglycerokinase, are considered to be essential for glycolysis and energy production under hypoxic conditions and adequate immune reaction in T cells, this TCR-mediated synthesis of HIF-1alpha may play a pivotal role in peripheral immune response. Taken together, our results may highlight a novel aspect of downstream signal from Ag recognition by TCR and a unique pharmacological role of rapamycin as well.
authors.affiliation: Division of Clinical Immunology, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakamura
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Makino
authors.forename: Kensaku
authors.initials: K
authors.lastname: Okamoto
authors.forename: Lorenz
authors.initials: L
authors.lastname: Poellinger
authors.forename: Kei
authors.initials: K
authors.lastname: Ohnuma
authors.forename: Chikao
authors.initials: C
authors.lastname: Morimoto
authors.forename: Hirotoshi
authors.initials: H
authors.lastname: Tanaka
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017252:CD3 Complex / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019169:Jurkat Cells; D019869:Phosphatidylinositol 3-Kinases / Q000097:blood / Q000502:physiology; D011494:Protein Kinases / Q000097:blood / Q000502:physiology; D011948:Receptors, Antigen, T-Cell / Q000097:blood / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D020123:Sirolimus / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D014162:Transfection
chemical_list: D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D019869:Phosphatidylinositol 3-Kinases; D011494:Protein Kinases; D011948:Receptors, Antigen, T-Cell; D020123:Sirolimus; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors; C497442:HIF1A protein, human; C546842:MTOR protein, human