Abstract
Interleukin 7 (IL-7) has a critical role in the development of early CD4(-)CD8(-) double-negative (DN) thymocytes. Although the transcription factor STAT5 is an important component of IL-7 signaling, differences in the phenotypes of mice deficient in STAT5, IL-7, IL-7 receptor alpha (IL-7rα) or the kinase Jak3 suggest the existence of STAT5-independent IL-7 signaling. Here we found that IL-7-Jak3 signals activated the transcription factor NFATc1 in DN thymocytes by phosphorylating Tyr371 in the regulatory region of NFATc1. This NFAT-activation pathway was critical for the survival and development of DN thymocytes, as deficiency in NFATc1 blocked thymocyte development at the DN1 stage, leading to T cell lymphopenia. In addition, our results demonstrated a cooperative function for NFATc1 and STAT5 in guiding thymocyte development in response to IL-7 signals.
Publication types
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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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Gene Expression Regulation
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Interleukin-7 / genetics*
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Interleukin-7 / immunology
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Janus Kinase 3 / genetics
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Janus Kinase 3 / immunology
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Lymphopenia / immunology
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Lymphopenia / pathology
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Mice
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Mice, Transgenic
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NFATC Transcription Factors / deficiency
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NFATC Transcription Factors / genetics*
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Phosphorylation
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Promoter Regions, Genetic
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Receptors, Interleukin-7 / genetics
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Receptors, Interleukin-7 / immunology
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STAT5 Transcription Factor / genetics*
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STAT5 Transcription Factor / immunology
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Signal Transduction / immunology*
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Thymocytes / cytology*
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Thymocytes / immunology
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Transcription, Genetic
Substances
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CD4 Antigens
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CD8 Antigens
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Interleukin-7
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NFATC Transcription Factors
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Nfatc1 protein, mouse
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Receptors, Interleukin-7
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STAT5 Transcription Factor
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interleukin-7, mouse
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Jak3 protein, mouse
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Janus Kinase 3