Abstract
The molecular process underlying T cell anergy is incompletely understood. Deltex1 (DTX1) is a Notch target with unknown physiological function. Here we show that Dtx1 was a transcription target of nuclear factor of activated T cells (NFAT) and participated in T cell anergy. DTX1 protein was upregulated during T cell anergy, and transgenic expression of Dtx1 attenuated T cell activation. DTX1 inhibited T cell activation by both E3-dependent and E3-independent mechanisms. In addition, DTX1 suppressed T cell activation in the absence of its Notch-binding domain. Importantly, DTX1 regulated the expression of two anergy-associated molecules, growth arrest and DNA-damage-inducible 45 beta (Gadd45 beta) and Cbl-b. DTX1 interacted with early growth response 2 (Egr-2) for optimum expression of Cbl-b. Furthermore, deficiency of DTX1 augmented T cell activation, conferred resistance to anergy induction, enhanced autoantibody generation, and increased inflammation. DTX1 therefore represents a component downstream of calcium-NFAT signaling that regulates T cell anergy.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / immunology
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Adaptor Proteins, Signal Transducing / metabolism
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Animals
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Antigens, Differentiation / immunology
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Antigens, Differentiation / metabolism
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Autoimmunity / immunology
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Clonal Anergy / genetics*
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DNA-Binding Proteins / genetics*
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DNA-Binding Proteins / immunology
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Early Growth Response Protein 2 / immunology
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Early Growth Response Protein 2 / metabolism
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Immediate-Early Proteins / immunology
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Immediate-Early Proteins / metabolism
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Inflammation / immunology
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Inflammation / metabolism
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Liver / immunology
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Liver / metabolism
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Liver / pathology
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Lung / immunology
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Lung / metabolism
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Lung / pathology
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Membrane Proteins / immunology
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Membrane Proteins / metabolism
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Mice
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Mice, Knockout
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Mice, Transgenic
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NFATC Transcription Factors / metabolism*
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Proto-Oncogene Proteins c-cbl / immunology
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Proto-Oncogene Proteins c-cbl / metabolism
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Ubiquitin-Protein Ligases
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Up-Regulation / immunology
Substances
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Adaptor Proteins, Signal Transducing
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Antigens, Differentiation
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Cblb protein, mouse
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DNA-Binding Proteins
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Early Growth Response Protein 2
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Egr2 protein, mouse
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Gadd45b protein, mouse
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Immediate-Early Proteins
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Laptm5 protein, mouse
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Membrane Proteins
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NFATC Transcription Factors
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Dtx1 protein, mouse
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Proto-Oncogene Proteins c-cbl
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Ubiquitin-Protein Ligases