Abstract
Notch signaling induces gene expression of the T cell lineage and discourages alternative fate outcomes. Hematopoietic deficiency in the Notch target Hes1 results in severe T cell lineage defects; however, the underlying mechanism is unknown. We found here that Hes1 constrained myeloid gene-expression programs in T cell progenitor cells, as deletion of the myeloid regulator C/EBP-α restored the development of T cells from Hes1-deficient progenitor cells. Repression of Cebpa by Hes1 required its DNA-binding and Groucho-recruitment domains. Hes1-deficient multipotent progenitor cells showed a developmental bias toward myeloid cells and dendritic cells after Notch signaling, whereas Hes1-deficient lymphoid progenitor cells required additional cytokine signaling for diversion into the myeloid lineage. Our findings establish the importance of constraining developmental programs of the myeloid lineage early in T cell development.
Publication types
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Research Support, N.I.H., Extramural
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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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CCAAT-Enhancer-Binding Protein-alpha / genetics
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CCAAT-Enhancer-Binding Protein-alpha / immunology*
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CCAAT-Enhancer-Binding Protein-alpha / metabolism
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Cell Line
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Cell Lineage / genetics
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Cell Lineage / immunology
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Cells, Cultured
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Cytokines / immunology
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Cytokines / metabolism
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Dendritic Cells / immunology
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Dendritic Cells / metabolism
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Female
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Flow Cytometry
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Gene Expression / immunology
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Homeodomain Proteins / genetics
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Homeodomain Proteins / immunology*
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Homeodomain Proteins / metabolism
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Lymphopoiesis / genetics
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Lymphopoiesis / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mutation
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Myeloid Cells / immunology
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Myeloid Cells / metabolism
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Protein Binding / immunology
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Receptor, Notch1 / genetics
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Receptor, Notch1 / immunology*
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Receptor, Notch1 / metabolism
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Reverse Transcriptase Polymerase Chain Reaction
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Signal Transduction / genetics
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Signal Transduction / immunology
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Stem Cells / immunology
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Stem Cells / metabolism
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T-Lymphocytes / immunology*
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T-Lymphocytes / metabolism
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Transcription Factor HES-1
Substances
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Basic Helix-Loop-Helix Transcription Factors
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CCAAT-Enhancer-Binding Protein-alpha
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Cytokines
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Hes1 protein, mouse
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Homeodomain Proteins
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Receptor, Notch1
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Transcription Factor HES-1