Abstract
TCR-induced NF-AT activation leads to the expression of both activating and inhibitory proteins. Previously, we had identified Egr-2 and Egr-3 as NF-AT-induced transcription factors which promote the inhibition of T cell activation. In this report we identify Sprouty1 as a downstream target of Egr-3. CD4⁺ T cells lacking Spry1 demonstrate enhanced proliferation and cytokine production. Likewise, Spry1(Flox/Flox) Lck Cre CD8⁺ T cells display increased cytolytic activity. Mechanistically, Spry1 acts at the level of PLC-γ promoting the inhibition of both Ca⁺⁺ induced NF-AT activation and MAP-kinase induced AP-1 activation while sparing NF-κB signaling. In vivo, mice in which Spry1 is selectively deleted in T cells demonstrate enhanced responses to a tumor vaccine and subsequently reject tumors more robustly than Wt mice. These findings suggest that targeting Spry1 might prove to be a novel means of enhancing tumor immunotherapy.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism*
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Cell Line, Tumor
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Early Growth Response Protein 3 / metabolism
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Gene Expression
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Membrane Proteins / genetics
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Membrane Proteins / metabolism*
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Mice
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NFATC Transcription Factors / metabolism
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Neoplasms / immunology
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Neoplasms / metabolism
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Phospholipase C gamma / metabolism
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Phosphoproteins / genetics
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Phosphoproteins / metabolism*
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Receptors, Antigen, T-Cell / metabolism
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T-Lymphocyte Subsets / immunology
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T-Lymphocyte Subsets / metabolism
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Transcription Factor AP-1 / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Membrane Proteins
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NFATC Transcription Factors
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Phosphoproteins
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Receptors, Antigen, T-Cell
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Spry1 protein, mouse
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Transcription Factor AP-1
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Early Growth Response Protein 3
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Phospholipase C gamma