Abstract
Earlier, we demonstrated the essential role of Kruppel-like transcription factor, TIEG1, in TGF-β-induced regulatory T cell (Treg) development. In this article, we demonstrate that IL-6, which promotes Th17 development, abrogated TIEG1 nuclear translocation and inhibited TGF-β-induced Treg development. Tyrosine kinase Tyk2-mediated phosphorylation of TIEG1 at Tyr179 promoted noncanonical K-27-linked polyubiquitination, which inhibited TIEG1 nuclear translocation. To test the role of TIEG1-regulated Treg/Th17 development in antitumor immunity, we analyzed TRAMP-C2 tumor growth in TIEG1(-/-) mice. The defective Treg development and elevated Th17 response resulted in enhanced immune reactivity in the tumor and inhibition of TRAMP-C2 tumor growth in TIEG1(-/-) mice. Thus, our results uncovered a novel regulatory mechanism that modulates Tregs and may regulate tumor progression.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Active Transport, Cell Nucleus
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Adoptive Transfer
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Animals
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Blotting, Western
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Cell Nucleus / metabolism
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Cell Proliferation*
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DNA-Binding Proteins / metabolism*
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Flow Cytometry
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Forkhead Transcription Factors / genetics*
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Forkhead Transcription Factors / metabolism
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Immunoprecipitation
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Interleukin-6 / metabolism
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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Neoplasms, Experimental / metabolism*
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Neoplasms, Experimental / pathology*
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Phosphorylation
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Polymerase Chain Reaction
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Receptors, Antigen, T-Cell / immunology
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Signal Transduction
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / metabolism
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TYK2 Kinase / metabolism
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Th17 Cells / metabolism
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Transcription Factors / metabolism*
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Transforming Growth Factor beta / metabolism
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Ubiquitination
Substances
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DNA-Binding Proteins
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Forkhead Transcription Factors
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Foxp3 protein, mouse
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Interleukin-6
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Receptors, Antigen, T-Cell
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Tieg1 protein, mouse
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Transcription Factors
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Transforming Growth Factor beta
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TYK2 Kinase