Abstract
During thymic T cell development, immature CD4+CD8+ double-positive (DP) thymocytes develop either into CD4+CD8- Th cells or CD4-CD8+ CTLs. Differentially expressed primary factors inducing the fate of these cell types are still poorly described. The transcription factor Runx3/AML-2 Runx, runt [corrected] dominant factor; AML, acute myeloid leukemia is expressed specifically during the development of CD8 single-positive (SP) thymocytes, where it silences CD4 expression. Deletion of murine Runx3 results in a reduction of CD8 SP T cells and concomitant accumulation of CD4+CD8+ T cells, which cannot down-regulate CD4 expression in the thymus and periphery. In this study we have investigated the role of Runx3 during thymocyte development and CD4 silencing and have identified integrin alpha(E)/CD103 on CD8 SP T cells as a new potential target gene of Runx3. We demonstrate that Runx3 is necessary not only to repress CD4, but also to induce CD103 expression during development of CD8 SP T cells. In addition, transgenic overexpression of Runx3 reduced CD4 expression during development of DP thymocytes, leading to a reduced number of CD4 SP thymocytes and an increased number of CD8 SP thymocytes. This reversal is not caused by redirection of specific MHC class II-restricted cells to the CD8 lineage. Overexpression of Runx3 also up-regulated CD103 expression on a subpopulation of CD4 SP T cells with characteristics of regulatory T cells. Thus, Runx3 is a main regulator of CD4 silencing and CD103 induction and thus contributes to the phenotype of CD8 SP T cells during thymocyte development.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amino Acid Sequence
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Animals
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Antigens, CD / biosynthesis*
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CD4 Antigens / biosynthesis*
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CD4 Antigens / genetics
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CD4-CD8 Ratio
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8 Antigens / biosynthesis
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CD8-Positive T-Lymphocytes / cytology*
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology*
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Cell Line, Tumor
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Cell Lineage / genetics
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Cell Lineage / immunology
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Core Binding Factor Alpha 3 Subunit
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Crosses, Genetic
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DNA-Binding Proteins / biosynthesis
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DNA-Binding Proteins / deficiency
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Down-Regulation / genetics
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Down-Regulation / immunology
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Gene Silencing
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Growth Inhibitors / biosynthesis
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Growth Inhibitors / deficiency
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Growth Inhibitors / genetics
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Growth Inhibitors / physiology
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Histocompatibility Antigens Class II / genetics
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Integrin alpha Chains / biosynthesis*
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Killer Cells, Natural / cytology
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Lymphopenia / genetics
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Lymphopenia / immunology
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Mice
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Transgenic
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Molecular Sequence Data
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Thymoma / genetics
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Thymoma / immunology
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
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Transcription Factors / biosynthesis
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Transcription Factors / deficiency
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Transcription Factors / genetics
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Transcription Factors / physiology*
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Transforming Growth Factor beta / physiology
Substances
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Antigens, CD
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CD4 Antigens
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CD8 Antigens
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Core Binding Factor Alpha 3 Subunit
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DNA-Binding Proteins
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Growth Inhibitors
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Histocompatibility Antigens Class II
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Integrin alpha Chains
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Runx3 protein, mouse
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Transcription Factors
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Transforming Growth Factor beta
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alpha E integrins