1. High levels of IL-7 cause dysregulation of thymocyte development
- Author
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Ronald E. Gress, Francis A. Flomerfelt, Veena Kapoor, Lee A. Hugar, Philip J. Lucas, Kevin S. Chua, Nahed El-Kassar, and Baishakhi Choudhury
- Subjects
medicine.medical_specialty ,T-Lymphocytes ,Cellular differentiation ,medicine.medical_treatment ,Transgene ,Immunology ,Cell ,Mice, Transgenic ,Suppressor of Cytokine Signaling Proteins ,Thymus Gland ,Biology ,Mice ,Internal medicine ,medicine ,Animals ,Immunology and Allergy ,Lymphopoiesis ,Receptor, Notch1 ,Progenitor cell ,Original Research ,B-Lymphocytes ,Thymocytes ,Interleukin-7 ,Cell Differentiation ,General Medicine ,Coculture Techniques ,Cell biology ,Mice, Inbred C57BL ,Thymocyte ,Cytokine ,medicine.anatomical_structure ,Endocrinology ,Stromal Cells ,Signal transduction ,Signal Transduction - Abstract
IL-7 signaling is required for thymocyte development and its loss has a severe deleterious effect on thymus function. Thymocyte–stromal cell interactions and other mechanisms tightly regulate IL-7 expression. We show that disruption of that regulation by over-expression of IL-7 inhibits T-cell development and promotes extensive B-cell lymphopoiesis in the thymus. Our data reveal that high levels of IL-7 negate Notch-1 function in thymocytes found in IL-7 transgenic mice and in co-culture with OP9-DL1 cells. While high levels of IL-7R are present on thymocytes, increased suppressor of cytokine signaling-1 expression blunts IL-7 downstream signaling, resulting in hypo-phosphorylation of proteins in the PI3K-Akt pathway. Consequently, GSK3β remains active and inhibits Notch-1 signaling as observed by decreased Hes-1 and Deltex expression in thymic progenitors. This is the first demonstration that high levels of IL-7 antagonize Notch-1 signaling and suggest that IL-7 may affect T- versus B-lineage choice in the thymus.
- Published
- 2012