Abstract
Signaling via the pre-T cell antigen receptor (pre-TCR) and the receptor Notch1 induces transient self-renewal (β-selection) of TCRβ(+) CD4(-)CD8(-) double-negative stage 3 (DN3) and DN4 progenitor cells that differentiate into CD4(+)CD8(+) double-positive (DP) thymocytes, which then rearrange the locus encoding the TCR α-chain (Tcra). Interleukin 7 (IL-7) promotes the survival of TCRβ(-) DN thymocytes by inducing expression of the pro-survival molecule Bcl-2, but the functions of IL-7 during β-selection have remained unclear. Here we found that IL-7 signaled TCRβ(+) DN3 and DN4 thymocytes to upregulate genes encoding molecules involved in cell growth and repressed the gene encoding the transcriptional repressor Bcl-6. Accordingly, IL-7-deficient DN4 cells lacked trophic receptors and did not proliferate but rearranged Tcra prematurely and differentiated rapidly. Deletion of Bcl6 partially restored the self-renewal of DN4 cells in the absence of IL-7, but overexpression of BCL2 did not. Thus, IL-7 critically acts cooperatively with signaling via the pre-TCR and Notch1 to coordinate proliferation, differentiation and Tcra recombination during β-selection.
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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CD4 Antigens / genetics
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CD4 Antigens / immunology
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CD8 Antigens / genetics
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CD8 Antigens / immunology
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Cell Differentiation
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Cell Proliferation
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Cell Survival
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Gene Expression Regulation
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Interleukin-7 / deficiency
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Interleukin-7 / genetics*
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Interleukin-7 / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Proto-Oncogene Proteins c-bcl-2 / genetics
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Proto-Oncogene Proteins c-bcl-2 / immunology
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Proto-Oncogene Proteins c-bcl-6 / deficiency
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Proto-Oncogene Proteins c-bcl-6 / genetics
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Proto-Oncogene Proteins c-bcl-6 / immunology
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Receptor, Notch1 / genetics*
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Receptor, Notch1 / 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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Recombination, Genetic
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Signal Transduction
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Thymocytes / cytology
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Thymocytes / immunology
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Thymocytes / metabolism*
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Thymus Gland / cytology
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Thymus Gland / immunology
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Thymus Gland / metabolism
Substances
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CD4 Antigens
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CD8 Antigens
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Interleukin-7
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Notch1 protein, mouse
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Proto-Oncogene Proteins c-bcl-2
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Proto-Oncogene Proteins c-bcl-6
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Receptor, Notch1
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Receptors, Antigen, T-Cell, alpha-beta
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interleukin-7, mouse
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Bcl2 protein, mouse