Abstract
Although the pathways that permit IL-2 production and the full activation of T cells upon Ag encounter are fairly well defined, the negative regulatory circuits that limit these pathways are poorly understood. In this study, we show that the E3 ubiquitin ligase adaptor Ndfip1 directs one such negative regulatory circuit. T cells lacking Ndfip1 produce IL-2, upregulate IL-2Rα, and proliferate, in the absence of CD28 costimulation. Furthermore, T cells in mice lacking both Ndfip1 and CD28 become activated, produce IL-4, and drive inflammation at barrier surfaces. Ndfip1 constrains T cell activation by limiting the duration of IL-2 mRNA expression after TCR stimulation. Ndfip1 and IL-2 have a similar expression pattern, and, following TCR stimulation, expression of both Ndfip1 and IL-2 requires the activity of NFAT and Erk. Taken together, these data support a negative regulatory circuit in which factors that induce IL-2 expression downstream of TCR engagement also induce the expression of Ndfip1 to limit the extent of IL-2 production and, thus, dampen T cell activation.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigen Presentation
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Antigens / immunology
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CD28 Antigens / biosynthesis
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CD28 Antigens / genetics
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CD28 Antigens / immunology*
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CD4-Positive T-Lymphocytes / immunology
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Carrier Proteins / physiology*
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Cells, Cultured
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Coculture Techniques
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Costimulatory and Inhibitory T-Cell Receptors / immunology
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Cyclosporine / pharmacology
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Feedback, Physiological
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Gene Expression Regulation / immunology*
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Hyaluronan Receptors / analysis
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Intercellular Signaling Peptides and Proteins
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Interleukin-2 / biosynthesis*
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Interleukin-2 / genetics
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Interleukin-2 Receptor alpha Subunit / biosynthesis
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Interleukin-2 Receptor alpha Subunit / genetics
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology*
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Lymphoid Tissue / immunology
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MAP Kinase Signaling System / drug effects
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MAP Kinase Signaling System / immunology
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Membrane Proteins / deficiency
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Membrane Proteins / physiology*
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Mice
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Mice, Knockout
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Mice, Transgenic
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NFATC Transcription Factors / immunology
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Ovalbumin / immunology
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Protein Kinase Inhibitors / pharmacology
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Ubiquitin-Protein Ligases / deficiency
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Ubiquitin-Protein Ligases / physiology
Substances
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Antigens
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CD28 Antigens
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Carrier Proteins
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Cd44 protein, mouse
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Costimulatory and Inhibitory T-Cell Receptors
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Hyaluronan Receptors
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Intercellular Signaling Peptides and Proteins
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Interleukin-2
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Interleukin-2 Receptor alpha Subunit
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Membrane Proteins
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NFATC Transcription Factors
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Ndfip1 protein, mouse
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Protein Kinase Inhibitors
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Cyclosporine
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Ovalbumin
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Itch protein, mouse
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Ubiquitin-Protein Ligases