Abstract
Antigen-specific Th1 cells could be a passage to the infection sites during infection to execute effector functions, such as help CD8+ T cells to localize in these sites by secretion of anti-viral cytokines-IFN-γ or direct cytotoxicity of antigen-bearing cells. However, the molecular components that modulate Th1 cell differentiation and function in response to viral infection remain incompletely understood. Here, we reported that both inhibitor of DNA binding 3(Id3) protein and inhibitor of DNA binding 2(Id2) protein promoted Th1 cell differentiation. Depletion of Id3 or Id2 led to severe defect of Th1 cell differentiation during influenza virus infection. Whereas depletion of both Id3 and Id2 in CD4+ T cells restrained Th1 cell differentiation to a greater extent, indicating that Id3 and Id2 nonredundantly regulate Th1 cell differentiation. Moreover, deletion of E-proteins, the antagonists of Id proteins, greatly enhanced Th1 cell differentiation. Mechanistic study indicated that E-proteins suppressed Th1 cell differentiation by directly binding to the regulatory elements of Th1 cell master regulator T-bet and regulate T-bet expression. Thus, our findings identified Id-protein's importance for Th1 cells and clarified the nonredundant role of Id3 and Id2 in regulating Th1 cell differentiation, providing novel insight that Id3-Id2-E protein axis are essential for Th1 cell polarization.
Keywords:
E-proteins; ID-proteins; Influenza virus infection; T-helper (Th)1; transcriptional regulation.
© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / immunology
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Basic Helix-Loop-Helix Transcription Factors / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD4-Positive T-Lymphocytes / virology
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / virology
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Gene Expression Regulation / immunology
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Inhibitor of Differentiation Protein 2 / genetics
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Inhibitor of Differentiation Protein 2 / immunology*
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Inhibitor of Differentiation Protein 2 / metabolism
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Inhibitor of Differentiation Proteins / genetics
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Inhibitor of Differentiation Proteins / immunology*
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Inhibitor of Differentiation Proteins / metabolism
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Mice, Knockout
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Mice, Transgenic
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Orthomyxoviridae / immunology*
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Orthomyxoviridae / physiology
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Orthomyxoviridae Infections / genetics
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Orthomyxoviridae Infections / immunology*
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Orthomyxoviridae Infections / virology
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Regulatory Elements, Transcriptional / genetics
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
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T-Box Domain Proteins / metabolism
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T-bet Transcription Factor
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Th1 Cells / immunology*
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Th1 Cells / metabolism
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Th1 Cells / virology
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Idb2 protein, mouse
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Inhibitor of Differentiation Protein 2
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Inhibitor of Differentiation Proteins
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T-Box Domain Proteins
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T-bet Transcription Factor
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Idb3 protein, mouse