Abstract
The differentiation of αβT cells from thymic precursors is a complex process essential for adaptive immunity. Here we exploited the breadth of expression data sets from the Immunological Genome Project to analyze how the differentiation of thymic precursors gives rise to mature T cell transcriptomes. We found that early T cell commitment was driven by unexpectedly gradual changes. In contrast, transit through the CD4(+)CD8(+) stage involved a global shutdown of housekeeping genes that is rare among cells of the immune system and correlated tightly with expression of the transcription factor c-Myc. Selection driven by major histocompatibility complex (MHC) molecules promoted a large-scale transcriptional reactivation. We identified distinct signatures that marked cells destined for positive selection versus apoptotic deletion. Differences in the expression of unexpectedly few genes accompanied commitment to the CD4(+) or CD8(+) lineage, a similarity that carried through to peripheral T cells and their activation, demonstrated by mass cytometry phosphoproteomics. The transcripts newly identified as encoding candidate mediators of key transitions help define the 'known unknowns' of thymocyte differentiation.
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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Antigens, CD / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / immunology
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Antigens, Differentiation, T-Lymphocyte / metabolism
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CD4-Positive T-Lymphocytes / immunology*
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CD4-Positive T-Lymphocytes / metabolism
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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 Lineage / genetics
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Cell Lineage / immunology
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Cell Proliferation
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Cells, Cultured
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Cluster Analysis
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Flow Cytometry
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Histocompatibility Antigens / genetics
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Histocompatibility Antigens / immunology
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Histocompatibility Antigens / metabolism
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Lectins, C-Type / immunology
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Lectins, C-Type / metabolism
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Male
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Mice
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Mice, Inbred C57BL
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Oligonucleotide Array Sequence Analysis
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Phosphorylation / immunology
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Receptors, Antigen, T-Cell, alpha-beta / genetics
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Receptors, Antigen, T-Cell, alpha-beta / immunology*
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Receptors, Antigen, T-Cell, alpha-beta / metabolism
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Thymocytes / cytology
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Thymocytes / immunology
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Thymocytes / metabolism
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Transcriptome / genetics
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Transcriptome / immunology
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD69 antigen
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Histocompatibility Antigens
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Lectins, C-Type
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Receptors, Antigen, T-Cell, alpha-beta