title: T cell hyporesponsiveness induced by oral administration of ovalbumin is associated with impaired NFAT nuclear translocation and p27kip1 degradation.
abstract: Oral tolerance is an important physiological component of the immune system whereby the organism avoids dangerous reactions such as hypersensitivity to ingested food proteins and other luminal Ags which may cause tissue damage and inflammation. In addition, it has been shown in animal models and in humans that oral tolerance can be applied to controlling undesired immune responses, including autoimmune diseases, allergies, and organ transplant rejections. However, the molecular mechanisms of oral tolerance have been poorly defined. In this study, we investigated the molecular basis underlying the hyporesponsiveness of orally tolerant CD4 T cells using a TCR transgenic mouse system in which oral tolerance was induced by long-term feeding with high dose Ag. We demonstrate that the hyporesponsive state of the CD4 T cells was maintained by a selective impairment in the TCR-induced calcium/NFAT signaling pathway and in the IL-2R-induced degradation of p27(kip1) and cell cycle progression. Thus, physiological mucosal tolerance is revealed to be associated with a unique type of T cell hyporesponsiveness which differs from previously described anergic T cells.
authors.affiliation: Department of Applied Biological Chemistry, Graduate School of Agricultural and Life Sciences, University of Tokyo, Japan.
authors.forename: Kazumi
authors.initials: K
authors.lastname: Asai
authors.forename: Satoshi
authors.initials: S
authors.lastname: Hachimura
authors.forename: Motoko
authors.initials: M
authors.lastname: Kimura
authors.forename: Terumasa
authors.initials: T
authors.lastname: Toraya
authors.forename: Masakatsu
authors.initials: M
authors.lastname: Yamashita
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kaminogawa
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D048868:Adaptor Proteins, Signal Transducing; D000284:Administration, Oral; D000595:Amino Acid Sequence; D000818:Animals; D000917:Antibody Formation / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D002352:Carrier Proteins / Q000378:metabolism; D002453:Cell Cycle / Q000235:genetics / Q000276:immunology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D017635:Clonal Anergy / Q000187:drug effects / Q000235:genetics; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004306:Dose-Response Relationship, Immunologic; D017874:Immediate-Early Proteins / Q000096:biosynthesis; D007376:Interleukin-2 / Q000494:pharmacology; D015759:Ionomycin / Q000494:pharmacology; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D048670:MAP Kinase Kinase 4; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008894:Milk Proteins; D020929:Mitogen-Activated Protein Kinase Kinases / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D008969:Molecular Sequence Data; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010047:Ovalbumin / Q000008:administration & dosage* / Q000276:immunology*; D051966:Phospholipase C gamma; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D050799:STAT5 Transcription Factor; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*; D010738:Type C Phospholipases / Q000037:antagonists & inhibitors / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D051746:ZAP-70 Protein-Tyrosine Kinase
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D018844:Cyclin-Dependent Kinases; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D007376:Interleukin-2; D015759:Ionomycin; D007527:Isoenzymes; D048670:MAP Kinase Kinase 4; D008565:Membrane Proteins; D008894:Milk Proteins; D020929:Mitogen-Activated Protein Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D010047:Ovalbumin; D051966:Phospholipase C gamma; D010750:Phosphoproteins; D011505:Protein-Tyrosine Kinases; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; D050799:STAT5 Transcription Factor; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D010738:Type C Phospholipases; D014443:Tyrosine; D051746:ZAP-70 Protein-Tyrosine Kinase; C493961:Cdkn1b protein, mouse; C491734:Lat protein, mouse; C054979:antigen T cell receptor, zeta chain; C497262:Zap70 protein, mouse; C482562:Map2k4 protein, mouse