Abstract
TCR gene rearrangement and expression are central to the development of clonal T lymphocytes. The pre-TCR complex provides the first signal instructing differentiation and proliferation events during the transition from CD4-CD8-TCR- double negative (DN) stage to CD4+CD8+ double positive (DP) stage. How the pre-TCR signal leads to downstream gene expression is not known. HeLa E-box binding protein (HEB), a basic helix-loop-helix transcription factor, is abundantly detected in thymocytes and is thought to regulate E-box sites present in many T cell-specific gene enhancers, including TCR-alpha, TCR-beta, and CD4. Targeted disruption of HEB results in a 5- to 10-fold reduction in thymic cellularity that can be accounted for by a developmental block at the DN to DP stage transition. Specifically, a dramatic increase in the CD4low/-CD8+CD5lowHSA+TCRlow/- immature single positive population and a concomitant decrease in the subsequent DP population are observed. Adoptive transfer test shows that this defect is cell-autonomous and restricted to the alpha beta T cell lineage. Introduction of an alpha beta TCR transgene into the HEBko/ko background is not sufficient to rescue the developmental delay. In vivo CD3 cross-linking analysis of thymocytes indicates that TCR signaling pathway in the HEBko/ko mice appears intact. These findings suggest an essential function of HEB in early T cell development, downstream or parallel to the pre-TCR signaling pathway.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adoptive Transfer
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Animals
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Antibodies, Monoclonal / administration & dosage
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Basic Helix-Loop-Helix Transcription Factors
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Female
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Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
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Helix-Loop-Helix Motifs
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Hematopoietic Stem Cell Transplantation
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Hematopoietic Stem Cells / cytology
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Hematopoietic Stem Cells / metabolism
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Hematopoietic Stem Cells / physiology*
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Hyaluronan Receptors / biosynthesis
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Hyaluronan Receptors / genetics
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Injections, Intraperitoneal
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Lymphocyte Count
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Receptor-CD3 Complex, Antigen, T-Cell / immunology
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / physiology*
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Receptors, Antigen, T-Cell, gamma-delta / genetics
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Receptors, Antigen, T-Cell, gamma-delta / physiology
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Receptors, Interleukin-2 / biosynthesis
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Receptors, Interleukin-2 / genetics
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Signal Transduction / genetics
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Signal Transduction / immunology*
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / metabolism
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T-Lymphocyte Subsets / physiology*
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Thymus Gland / cytology*
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Thymus Gland / metabolism
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Thymus Gland / physiology*
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Transcription Factors / biosynthesis
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transgenes / immunology
Substances
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Antibodies, Monoclonal
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Basic Helix-Loop-Helix Transcription Factors
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DNA-Binding Proteins
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Hyaluronan Receptors
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Receptor-CD3 Complex, Antigen, T-Cell
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Receptors, Antigen, T-Cell, alpha-beta
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Receptors, Antigen, T-Cell, gamma-delta
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Receptors, Interleukin-2
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Tcf12 protein, mouse
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Transcription Factors