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.
MeSH terms
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Active Transport, Cell Nucleus / drug effects
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Active Transport, Cell Nucleus / genetics
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Active Transport, Cell Nucleus / immunology
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Adaptor Proteins, Signal Transducing*
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Administration, Oral
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Amino Acid Sequence
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Animals
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Antibody Formation / genetics
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CD4-Positive T-Lymphocytes / drug effects
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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Calcium Signaling / drug effects
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Calcium Signaling / genetics
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Calcium Signaling / immunology
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Carrier Proteins / metabolism
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Cell Cycle / genetics
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Cell Cycle / immunology
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Cell Cycle Proteins / metabolism*
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Clonal Anergy* / drug effects
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Clonal Anergy* / genetics
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Cyclin-Dependent Kinase Inhibitor p27
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Cyclin-Dependent Kinases / antagonists & inhibitors
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DNA-Binding Proteins / antagonists & inhibitors
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DNA-Binding Proteins / metabolism*
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Dose-Response Relationship, Immunologic
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Immediate-Early Proteins / biosynthesis
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Interleukin-2 / pharmacology
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Ionomycin / pharmacology
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Isoenzymes / antagonists & inhibitors
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Isoenzymes / metabolism
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MAP Kinase Kinase 4*
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MAP Kinase Signaling System / genetics
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MAP Kinase Signaling System / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Inbred BALB C
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Mice, Knockout
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Mice, Transgenic
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Milk Proteins*
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Mitogen-Activated Protein Kinase Kinases / physiology
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Mitogen-Activated Protein Kinases / physiology
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Molecular Sequence Data
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NFATC Transcription Factors
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Nuclear Proteins*
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Ovalbumin / administration & dosage*
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Ovalbumin / immunology*
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Phospholipase C gamma
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Phosphoproteins / metabolism
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Phosphorylation
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Protein-Tyrosine Kinases / metabolism
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Receptors, Antigen, T-Cell / metabolism
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Interleukin-2 / biosynthesis
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STAT5 Transcription Factor
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Spleen / cytology
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Spleen / immunology
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Spleen / metabolism
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators / metabolism
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Transcription Factors / antagonists & inhibitors
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Transcription Factors / metabolism*
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Tumor Suppressor Proteins / metabolism*
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Type C Phospholipases / antagonists & inhibitors
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Type C Phospholipases / metabolism
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Tyrosine / metabolism
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Adaptor Proteins, Signal Transducing
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Carrier Proteins
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Cdkn1b protein, mouse
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Cell Cycle Proteins
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DNA-Binding Proteins
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Immediate-Early Proteins
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Interleukin-2
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Isoenzymes
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Lat protein, mouse
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Membrane Proteins
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Milk Proteins
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NFATC Transcription Factors
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Nuclear Proteins
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Phosphoproteins
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Receptors, Antigen, T-Cell
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Interleukin-2
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STAT5 Transcription Factor
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Suppressor of Cytokine Signaling Proteins
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Trans-Activators
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Transcription Factors
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Tumor Suppressor Proteins
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antigen T cell receptor, zeta chain
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cytokine inducible SH2-containing protein
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Cyclin-Dependent Kinase Inhibitor p27
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Tyrosine
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Ionomycin
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Ovalbumin
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Protein-Tyrosine Kinases
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ZAP-70 Protein-Tyrosine Kinase
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Zap70 protein, mouse
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Cyclin-Dependent Kinases
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Mitogen-Activated Protein Kinases
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MAP Kinase Kinase 4
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Map2k4 protein, mouse
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Mitogen-Activated Protein Kinase Kinases
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Type C Phospholipases
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Phospholipase C gamma